Global diversity and evidence for coevolution of KIR and HLA.

The killer immunoglobulin-like receptor (KIR ) gene cluster shows extensive genetic diversity, as do the HLA class I loci, which encode ligands for KIR molecules. We genotyped 1,642 individuals from 30 geographically distinct populations to examine population-level evidence for coevolution of these two functionally related but unlinked gene clusters. We observed strong negative correlations between the presence of activating KIR genes and their corresponding HLA ligand groups across populations, especially KIR3DS1 and its putative HLA-B Bw480I ligands (r ¼ –0.66, P ¼ 0.038). In contrast, we observed weak positive relationships between the various inhibitory KIR genes and their ligands. We observed a negative correlation between distance from East Africa and frequency of activating KIR genes and their corresponding ligands, suggesting a balance between selection on HLA and KIR loci. Most KIR-HLA genetic association studies indicate a primary influence of activating KIR-HLA genotypes in disease risk 1,2 ; concomitantly, activating receptor-ligand pairs in this study show the strongest signature of coevolution of these two complex genetic systems as compared with inhibitory receptor-ligand pairs. The KIR genes located on chromosome 19q13.4 encode activating and inhibitory receptors that are expressed on natural killer (NK) cells and a subset of T cells. The KIR gene cluster shows extensive variability in terms of gene content across haplotypes, probably because of nonallelic homologous recombination occurring between pairs of homologous KIR genes 3 . Over 30 distinct KIR haplotypes have been identified based on gene content alone 4 , among which the most salient distinction is the presence or absence of various activating receptor genes. HLA class I genes are characterized by extreme allelic polymorphism and encode molecules that bind T cell receptors on cytotoxic T lymphocytes, thereby initiating acquired immune responses. More recently, HLA allotypes have been shown to serve as ligands for KIR, establishing their importance in both the innate and acquired immune response. The extreme variability at KIR and HLA loci is thought to provide protection against a wide variety of pathogens, with different KIR-HLA combinations conferring protection against distinct diseases. Several models for the maintenance of this degree of diversity have been posited, including frequencydependent selection, heterozygote advantage and selection varying in time and space 5‐7 . Overall, the concept of different KIR-HLA combinations protecting against distinct diseases is supported by disease