KIR genes

The KIR locus on chromosome 19 spans up to 14 genes that are not all present in every person. Two haplotype groups are distinguished: A haplotypes carry a largely fixed, mostly inhibitory gene set, while B haplotypes additionally carry more activating KIR and vary more in content and arrangement. This diversity arises from gene duplication and deletion together with high allelic polymorphism and makes KIR as demanding as HLA. Every person inherits one KIR haplotype from each parent, so the individual repertoire varies widely.

Genome uses T1K (Song et al., 2023), which determines KIR and HLA alleles directly from short reads by matching the reads against the IPD-KIR and the IPD-IMGT/HLA reference databases. T1K first gathers candidate reads through short sequence matches (seeds) and assigns them to the alleles with the most matching nucleotides. A weighted expectation-maximization algorithm then estimates allele abundances for all genes at once, so reads that fit several highly similar KIR genes are handled jointly rather than in isolation. Per locus T1K selects the allele pair that explains the most reads, filters weak candidates below a fraction of the dominant allele and assigns a quality score to each call. Genome presents these calls as independent technical evidence, separate from any clinical interpretation.

KIR genotyping cannot be solved with the usual variant pipelines that assume a single reference genome. First, KIR genes are very similar to each other, so short reads often fit several genes equally well, for example the closely related KIR2DL5A and KIR2DL5B. Second, individual KIR genes can be entirely absent from a chromosome, so the tool must infer presence or absence from read coverage rather than only distinguishing alleles. Third, allelic diversity is high and grows with every IPD-KIR update. T1K addresses this by modelling all genes jointly: low estimated abundance points to a missing gene, and the simultaneous estimation separates homologous genes that could not be resolved on their own.