Allele imputation for the killer cell immunoglobulin-like receptor KIR3DL1/S1

• Published in: PLoS computational biology 2022-02, Vol.18 (2), p.e1009059
• Main Authors: Harrison, Genelle F, Leaton, Laura Ann, Harrison, Erica A, Kichula, Katherine M, Viken, Marte K, Shortt, Jonathan, Gignoux, Christopher R, Lie, Benedicte A, Vukcevic, Damjan, Leslie, Stephen, Norman, Paul J
• Format: Article
• Language: English
• Subjects: Algorithms; Alleles; Allelomorphism; Biology and Life Sciences; Cancer; Cell receptors; Chromosomes; Combinatorial analysis; Ecology and Environmental Sciences; Gene frequency; Genetic aspects; Genetic diversity; Genomes; Genomics; Genotype; Genotype & phenotype; Genotypes; Genotyping; Haplotypes; High resolution; Histocompatibility antigen HLA; HLA-B Antigens - genetics; Humans; Immunotherapy; Killer cells; Lymphocytes; Lymphocytes T; Medicine and health sciences; Natural killer cells; Physiological aspects; Polymorphism; Population; Potassium channels (inwardly-rectifying); Receptors; Receptors, KIR - genetics; Receptors, KIR3DL1 - genetics; Receptors, KIR3DS1 - genetics; S1 gene; Signal transduction; Single-nucleotide polymorphism; Transplantation; Viral infections
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1009059

Highly polymorphic interaction of KIR3DL1 and KIR3DS1 with HLA class I ligands modulates the effector functions of natural killer (NK) cells and some T cells. This genetically determined diversity affects severity of infections, immune-mediated diseases, and some cancers, and impacts the course of immunotherapies, including transplantation. KIR3DL1 is an inhibitory receptor, and KIR3DS1 is an activating receptor encoded by the KIR3DL1/S1 gene that has more than 200 diverse and divergent alleles. Determination of KIR3DL1/S1 genotypes for medical application is hampered by complex sequence and structural variation, requiring targeted approaches to generate and analyze high-resolution allele data. To overcome these obstacles, we developed and optimized a model for imputing KIR3DL1/S1 alleles at high-resolution from whole-genome SNP data. We designed the model to represent a substantial component of human genetic diversity. Our Global imputation model is effective at genotyping KIR3DL1/S1 alleles with an accuracy ranging from 88% in Africans to 97% in East Asians, with mean specificity of 99% and sensitivity of 95% for alleles >1% frequency. We used the established algorithm of the HIBAG program, in a modification named Pulling Out Natural killer cell Genomics (PONG). Because HIBAG was designed to impute HLA alleles also from whole-genome SNP data, PONG allows combinatorial diversity of KIR3DL1/S1 with HLA-A and -B to be analyzed using complementary techniques on a single data source. The use of PONG thus negates the need for targeted sequencing data in very large-scale association studies where such methods might not be tractable.