Year: 2026
Type: preprint
Abstract: Pangenome graphs built from haplotype-resolved de novo assemblies enable accurate analysis of genetic variation. The short-read-based tool PanGenie efficiently genotypes variants discovered in a pangenome across large cohorts and outperforms linear reference-based methods for structural variants (SVs). However, it cannot detect novel variants absent from the graph, missing many rare SVs (allele frequency <1%) and was limited to graphs with 254 haplotypes. First, we introduce a haplotype sampling step that reduces the number of haplotypes using sample-specific k-mers before genotyping, decreasing runtime twelvefold and memory usage 1.4-fold at 30x coverage. Second, we present a polishing workflow that corrects residual errors in haplotypes inferred from PanGenie genotypes and incorporates rare and private mutations. We genotype 3,202 samples from the 1000 Genomes Project and use low-coverage ONT data (967 samples) for polishing. We achieve a median QV of 46 and provide the 1,934 polished haplotype sequences as a community resource.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Building Tools and Community to Make Pangenomes Accessible, Tooling for accurately studying the epigenome along the human pangenome reference, Center for Human Reference Genome Diversity, Integrating the reference pangenome with biobank-scale data for complex trait analysis, Telomere-to-telomere assemblies of human genomes, Tools for comprehensive variant characterization using the pangenome, The Human Pangenome Reference Consortium Coordination Center
OpenAlex ID: W7167215822