Population-scalable genotyping from low-coverage sequencing data using pangenome graphs

Abstract

Pangenome-based genotyping of structurally complex loci remains challenging at low sequencing depths, particularly when samples are of low quality, such as in ancient DNA. We present COSIGT (COsine SImilarity-based GenoTyper), a method that infers structural genotypes by matching short-read coverage patterns to pangenome haplotypes using cosine similarity. COSIGT maintains robust accuracy at low coverage (1-2X), outperforming existing methods where depth-sensitive approaches degrade. We demonstrate scalability to thousands of modern and ancient genomes, enabling population-scale analyses of complex variation from low-coverage data.