Geny: A Genotyping Tool for Allelic Decomposition of Killer Cell Immunoglobulin-Like Receptor Genes

Abstract

AbstractAccurate genotyping of Killer cell Immunoglobulin-like Receptor (KIR) genes plays a pivotal role in enhancing our understanding of innate immune responses, disease correlations, and the advancement of personalized medicine. However, due to the high variability of the KIR region and high level of sequence similarity among different KIR genes, the currently available genotyping methods are unable to accurately infer copy numbers, genotypes and haplotypes of individual KIR genes from next-generation sequencing data. Here we introduce Geny, a new computational tool for precise genotyping of KIR genes. Geny utilizes available KIR haplotype databases and proposes a novel combination of expectation-maximization filtering schemes and integer linear programming-based combinatorial optimization models to resolve ambiguous reads, provide accurate copy number estimation and estimate the haplotype of each copy for the genes within the KIR region. We evaluated Geny on a large set of simulated short-read datasets covering the known validated KIR region assemblies and a set of Illumina short-read samples sequenced from 25 validated samples from the Human Pangenome Reference Consortium collection and showed that it outperforms the existing genotyping tools in terms of accuracy, precision and recall. We envision Geny becoming a valuable resource for understanding immune system response and consequently advancing the field of patient-centric medicine.