Original Paper

Immunogenetics

, Volume 56, Issue 4, pp 225-237

SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex

  • Paul J. NormanAffiliated withClinical Transplantation Laboratory, Guy’s Hospital Email author 
  • , Mark A. CookAffiliated withCancer Research UK Institute for Cancer Studies, University of BirminghamHistocompatibility and Immunogenetics, National Blood Service
  • , B. Sean CareyAffiliated withClinical Transplantation Laboratory, Guy’s HospitalInstitute of Urology and Nephrology, University College
  • , Christine V. F. CarringtonAffiliated withDepartment of Pre-Clinical Sciences, Faculty of Medical Sciences, University of the West Indies
  • , David H. VerityAffiliated withDepartment of Opthalmology, St Thomas’ Hospital-King’s College
  • , Kamran HameedAffiliated withDepartment of Medicine, Aga Khan University Hospital
  • , D. Dan RamdathAffiliated withDepartment of Pre-Clinical Sciences, Faculty of Medical Sciences, University of the West Indies
  • , Dasnayanee ChandanayingyongAffiliated withDepartment of Transfusion Medicine, Siriraj Hospital
  • , Mark LeppertAffiliated withEccles Centre for Human Genetics, University of Utah
    • , Henry A. F. StephensAffiliated withClinical Transplantation Laboratory, Guy’s HospitalInstitute of Urology and Nephrology, University College
    • , R. W. VaughanAffiliated withClinical Transplantation Laboratory, Guy’s Hospital Email author 

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Abstract

The human leukocyte receptor complex (LRC) of Chromosome 19q13.4 encodes polymorphic and highly homologous genes that are expressed by cells of the immune system and regulate their function. There is an enormous diversity at the LRC, most particularly the variable number of killer cell immunoglobulin-like receptor (KIR) genes. KIR have been associated with several disease processes due to their interaction with polymorphic human leukocyte antigen class I molecules. We have assessed haplotype compositions, linkage disequilibrium patterns and allele frequencies in two Caucasoid population samples (n=54, n=100), using a composite of single-nucleotide polymorphism (SNP) markers and high-resolution, allele-specific molecular genotyping. Particular KIR loci segregated with SNP and other markers, forming two blocks that were separated by a region with a greater history of recombination. The KIR haplotype composition and allele frequency distributions were consistent with KIR having been subject to balancing selection (Watterson’s F: P=0.001). In contrast, there was a high inter-population heterogeneity measure for the LRC-encoded leukocyte immunoglobulin-like receptor A3 (LILRA3), indicating pathogen-driven disruptive selection (Wright’s F ST=0.32). An assessment of seven populations representative of African, Asian and Caucasoid ethnic groups (total n=593) provided little evidence for long-range LRC haplotypes. The different natural selection pressures acting on each locus may have contributed to a lack of linkage disequilibrium between them.

Keywords

KIR Leukocyte receptor complex Natural killer cell SNP Haplotype Natural selection