STR-PG: A Topology-decoupled Pangenome Framework for Scalable Short-read Genotyping of Short Tandem Repeats

Short tandem repeats (STRs) are a rich and highly polymorphic source of human genetic variation, but representing and genotyping them in pangenome graphs remains challenging. Explicitly encoding each STR allele as a separate graph path results in increasingly complex local structures as cohort diversity increases, leading to larger index sizes and requiring significant resources for graph reconstruction when new alleles are introduced. Here, we propose STR-PG, a topologically decoupled genome-wide framework that separates stable locus representation from scalable STR allele content. STR-PG uses topologically fixed pointer nodes to represent each target locus, while allele sequences, repeat counts, motif annotations, and population frequency metadata are stored in an external registry. Short reads are mapped to STR loci via syncmer-based flanking anchors, and genotyping is performed within a locus-specific candidate space using allele-level alignment likelihood and Bayesian inference. Newly supported alleles can be integrated through registry-level updates without the need to rebuild the graph structure. Evaluations using simulated whole-genome sequencing data, 1000 Genomes Project (1kGP) samples, and r real whole-exome sequencing data from matched whole-blood-cell controls demonstrate that STR-PG maintains accurate genotyping results across various STR classes, reproduces expected population structures, and substantially reduces the computational cost of integrating additional alleles. STR-PG provides a compact and scalable framework for population-scale STR analysis using short-read sequencing.