Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans.
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.
Norman
Paul J
PJ
Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA. paul.norman@stanford.edu
Abi-Rached
Laurent
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Michael
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Chang
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Matamoros
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D000483:Alleles; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D044383:Black People / Q000235:genetics*; D005787:Gene Frequency; D005828:Genetics, Population; D015235:HLA-B Antigens / Q000737:chemistry / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D054341:Receptors, KIR3DL1 / Q000737:chemistry / Q000235:genetics*; D054349:Receptors, KIR3DS1 / Q000737:chemistry / Q000235:genetics*; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid
D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1