title: SNP haplotypes and allele frequencies show evidence for disruptive and balancing selection in the human leukocyte receptor complex.
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 FST=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.
authors.affiliation: Clinical Transplantation Laboratory, Guy's Hospital, 3rd Floor New Guy's House, St. Thomas' Street, London, SE1 9RT, UK. paul.norman@stanford.edu
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Cook
authors.forename: B Sean
authors.initials: BS
authors.lastname: Carey
authors.forename: Christine V F
authors.initials: CV
authors.lastname: Carrington
authors.forename: David H
authors.initials: DH
authors.lastname: Verity
authors.forename: Kamran
authors.initials: K
authors.lastname: Hameed
authors.forename: D Dan
authors.initials: DD
authors.lastname: Ramdath
authors.forename: Dasnayanee
authors.initials: D
authors.lastname: Chandanayingyong
authors.forename: Mark
authors.initials: M
authors.lastname: Leppert
authors.forename: Henry A F
authors.initials: HA
authors.lastname: Stephens
authors.forename: R W
authors.initials: RW
authors.lastname: Vaughan
mesh_terms: D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D007962:Leukocytes / Q000276:immunology*; D015810:Linkage Disequilibrium; D018895:Microsatellite Repeats; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology; D012641:Selection, Genetic; D006113:United Kingdom / Q000208:ethnology; D044465:White People
chemical_list: D011971:Receptors, Immunologic