Privacy-preserving pangenome graphs

Abstract The human pangenome reference, often represented as a graph, promises to capture genetic diversity across populations, but open release of individual haplotypes raises significant privacy concerns, including risks of re-identification and inference of sensitive traits. To address these challenges, we introduce PanMixer, a framework for privacy-preserving pangenome graph releases that selectively obfuscates an individual’s haplotypes while retaining the utility of the reference graph. PanMixer formulates the privacy-utility trade-off as a knapsack problem, where privacy risk is quantified using information-theoretic measures and utility is measured using graph properties. Using the recently released draft human pangenome graphs, we show that PanMixer robustly reduces re-identification risk under linkage attacks and genome reconstruction attempts. We also show that PanMixer preserves the accuracy of key downstream applications, including allele frequency estimation, linkage disequilibrium analysis, and read mapping. By addressing privacy concerns, PanMixer enables the inclusion of individuals, particularly those from underrepresented populations, who might otherwise be reluctant to contribute but seek representation in future genomic studies. Our results provide both a practical tool and a generalizable framework for balancing privacy and utility in future large-scale pangenome references.