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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 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 risk1,2; 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.

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Figure 1: Map of the world showing the location of sampled populations.
Figure 2: KIR and HLA ligand carrier frequencies across populations.
Figure 3: Correlation between KIR and HLA ligand frequencies.


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We thank H. Rajeevan and M. Osier for their assistance with the ALFRED database. This project has been funded in whole or in part with federal funds from the US National Cancer Institute (National Institutes of Health) under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. R.M.S. was supported by NIH grant GM35326, Department of Energy grant DE-FG02-00ER45828 and the Vermont Advanced Computing Center under NASA grant NNG-05GO96G. D.M. was supported by FAPESP grant 03/08973-6.

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M.C. designed and supervised the project and prepared the manuscript; R.M.S. contributed to the design of the project, developed the statistical methods and prepared the manuscript; M.P.M. performed KIR genotyping and prepared the manuscript; X.G. performed HLA genotyping; D.M. and M.Y. provided intellectual input; J.R.K. and K.K.K. provided samples and intellectual input; all authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Mary Carrington.

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The authors declare no competing financial interests.

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Single, R., Martin, M., Gao, X. et al. Global diversity and evidence for coevolution of KIR and HLA. Nat Genet 39, 1114–1119 (2007).

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