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

Bolognini, D.; Guarracino, A.; Paleni, C.; Dudley, T. S.; Iacoviello, L.; Raveane, A.; Sudmant, P. H.; Garrison, E.; Soranzo, N.

2026-02-06 bioinformatics
10.64898/2026.02.05.704023 bioRxiv
Show 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.

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