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 Bw4-80I ligands (r = -0.66, P = 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.

1. The Department of Mathematics and Statistics, University of Vermont, Burlington, Vermont 05405, USA.
2. Laboratory of Genomic Diversity, SAIC-Frederick, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
3. Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo, Rua do Matão 277, São Paulo, SP 05608-900 Brazil.
4. Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Maryland 21702, USA.
5. Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20852, USA.
6. Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
7. These authors contributed equally to this work.

Correspondence to: Mary Carrington² e-mail: carringt@ncifcrf.gov

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