Locityper enables targeted genotyping of complex polymorphic genes.

Area of Science:

• Genomics
• Bioinformatics
• Medical Genetics

Background:

• The human genome has structurally variable polymorphic loci, including disease-associated genes, that are difficult for accurate variant calling.
• Existing variant calling pipelines struggle with these complex genomic regions.

Purpose of the Study:

• To introduce Locityper, a novel computational tool for genotyping challenging polymorphic loci in the human genome.
• To enable accurate variant calling in disease-associated genes previously inaccessible to standard methods.

Main Methods:

• Locityper utilizes short-read and long-read whole-genome sequencing data.
• It recruits and aligns sequencing reads to locus haplotypes, optimizing alignment, insert size, and read depth profiles.
• The tool genotypes target loci by finding the likeliest haplotype pair.

Main Results:

• Locityper achieved a median quality value (QV) above 35 for 256 challenging medically relevant loci using both long-read and short-read data.
• It outperformed state-of-the-art Illumina and PacBio HiFi variant calling pipelines.
• The tool demonstrated efficient genotyping of hyperpolymorphic genes like HLA, KIR, MUC, and FCGR.

Conclusions:

• Locityper provides accurate genotyping for structurally variable and disease-associated genes in the human genome.
• Its scalability and speed make it suitable for large-scale biobank studies.
• The tool facilitates genetic association studies for previously intractable disease-relevant genes.