Meiotic recombination generates rich diversity in NK cell receptor genes, alleles, and haplotypes

Paul J Norman, Laurent Abi-Rached, Ketevan Gendzekhadze, John A Hammond, Achim K Moesta, Deepti Sharma, Thorsten Graef, Karina L McQueen, Lisbeth A Guethlein, Christine V F Carrington, Dasdayanee Chandanayingyong, Yih-Hsin Chang, Catalina Crespí, Güher Saruhan-Direskeneli, Kamran Hameed, Giorgi Kamkamidze, Kwadwo A Koram, Zulay Layrisse, Nuria Matamoros, Joan MilàMyoung Hee Park, Ramasamy M Pitchappan, D Dan Ramdath, Ming-Yuh Shiau, Henry A F Stephens, Siske Struik, Dolly Tyan, David H Verity, Robert W Vaughan, Ronald W Davis, Patricia A Fraser, Eleanor M Riley, Mostafa Ronaghi, Peter Parham

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric "half" was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family.

Original languageEnglish
Pages (from-to)757-69
Number of pages13
JournalGenome Research
Volume19
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • Alleles
  • Amino Acid Sequence
  • Cell Line
  • Evolution, Molecular
  • Genetic Variation/genetics
  • Haplotypes/genetics
  • Humans
  • Meiosis/genetics
  • Models, Genetic
  • Molecular Sequence Data
  • Phenotype
  • Receptors, KIR/genetics
  • Receptors, KIR3DL1/genetics
  • Receptors, Natural Killer Cell/genetics
  • Recombination, Genetic/genetics

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