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


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)1092-9
Number of pages8
JournalNature Genetics
Issue number9
Publication statusPublished - Sep 2007


  • African Continental Ancestry Group/genetics
  • Alleles
  • Amino Acid Sequence
  • Binding Sites/genetics
  • Gene Frequency
  • Genetics, Population
  • HLA-B Antigens/chemistry
  • Humans
  • Linkage Disequilibrium
  • Molecular Sequence Data
  • Phylogeny
  • Polymorphism, Genetic
  • Protein Structure, Tertiary
  • Receptors, KIR3DL1/chemistry
  • Receptors, KIR3DS1/chemistry
  • Selection, Genetic
  • Sequence Homology, Amino Acid


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