StarPhase: Comprehensive Phase-Aware Pharmacogenomic Diplotyper for Long-Read Sequencing Data
Holt, J. M.; Harting, J.; Chen, X.; Baker, D.; Saunders, C. T.; Kronenberg, Z.; Gonzaludo, N.; Yoo, B.; Hudjashov, G.; Joeloo, M.; Lawlor, J. M. J.; Lim, W. K.; Estonian Biobank Research Team, ; Jamuar, S. S.; Cooper, G. M.; Milani, L.; Pastinen, T.; Eberle, M. A.
Show abstract
Pharmacogenomics is central to precision medicine, informing medication safety and efficacy. Phar-macogenomic diplotyping of complex genes requires full-length DNA sequences and detection of structural rearrangements. We introduce StarPhase, a tool that leverages PacBio HiFi sequence data to diplotype 21 CPIC Level A pharmacogenes and provides detailed haplotypes and supporting visualizations for HLA-A, HLA-B, and CYP2D6. StarPhase diplotypes have high concordance with benchmarks where 99.5% are either exact matches or minor discrepancies. Manual inspection of the 0.5% mismatches indicates they were correctly called by StarPhase. With StarPhase, we update or correct 26.2% of GeT-RM pharmacogenomic diplotypes. Population distributions from StarPhase mostly reflect those of the All of Us cohort, while also highlighting gaps in existing pharmacogenomic databases that long-read sequencing can fill. With a single HiFi whole genome sequencing assay, StarPhase enables robust PGx diplotyping even as additional pharmacogenes and haplotypes are discovered.
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