Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans

Paul J. Norman, Laurent Abi-Rached, Ketevan Gendzekhadze, Daniel Korbel, Michael Gleimer, Don Rowley, Dan Bruno, Christine V.F. Carrington, Dasdayanee Chandanayingyong, Yih Hsin Chang, Catalina Crespí, Güher Saruhan-Direskeneli, Patricia A. Fraser, Kamran Hameed, Giorgi Kamkamidze, Kwadwo A. Koram, Zulay Layrisse, Nuria Matamoros, Joan Milà, Myoung Hee ParkRamasamy M. Pitchappan, D. Dan Ramdath, Ming Yuh Shiau, Henry A.F. Stephens, Siske Struik, David H. Verity, Robert W. Vaughan, Dolly Tyan, Ronald W. Davis, Eleanor M. Riley, Mostafa Ronaghi, Peter Parham

Research output: Contribution to journalArticlepeer-review

194 Citations (Scopus)


Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.

Original languageEnglish
Pages (from-to)1092-1099
Number of pages8
JournalNature Genetics
Issue number9
Publication statusPublished - Sept 2007


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