High-Resolution Characterization of KIR Genes in a Large North American Cohort Reveals Novel Details of Structural and Sequence Diversity

The <i>KIR (killer-cell immunoglobulin-like receptor</i>) region is characterized by structural variation and high sequence similarity among genes, imposing technical difficulties for analysis. We undertook the most comprehensive study to date of <i>KIR</i> genetic diversity in a large population sample, applying next-generation sequencing in 2,130 United States European-descendant individuals. Data were analyzed using our custom bioinformatics pipeline specifically designed to address technical obstacles in determining <i>KIR</i> genotypes. Precise gene copy number determination allowed us to identify a set of uncommon gene-content <i>KIR</i> haplotypes accounting for 5.2% of structural variation. In this cohort, <i>KIR2DL4</i> is the framework gene that most varies in copy number (6.5% of all individuals). We identified phased high-resolution alleles in large multi-locus insertions and also likely founder haplotypes from which they were deleted. Additionally, we observed 250 alleles at 5-digit resolution, of which 90 have frequencies ≥1%. We found sequence patterns that were consistent with the presence of novel alleles in 398 (18.7%) individuals and contextualized multiple orphan dbSNPs within the <i>KIR</i> complex. We also identified a novel KIR2DL1 variant, Pro151Arg, and demonstrated by molecular dynamics that this substitution is predicted to affect interaction with HLA-C. No previous studies have fully explored the full range of structural and sequence variation of <i>KIR</i> as we present here. We demonstrate that pairing high-throughput sequencing with state-of-art computational tools in a large cohort permits exploration of all aspects of <i>KIR</i> variation including determination of population-level haplotype diversity, improving understanding of the <i>KIR</i> system, and providing an important reference for future studies.