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(KIR) and HLA Class I Genes

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(KIR) and HLA Class I Genes Genes and Immunity (2010) 11, 467–478 & 2010 Macmillan Publishers Limited All rights reserved 1466-4879/10 www.nature.com/gene ORIGINAL ARTICLE Signatures of natural selection and coevolution between killer cell immunoglobulin-like receptors (KIR) and HLA class I genes KJ Guinan1, RT Cunningham2,4, A Meenagh2, A Gonzalez2, MM Dring1, BW McGuinness1, D Middleton3 and CM Gardiner1 1School of Biochemistry and Immunology, Trinity College, Dublin, Ireland; 2Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, Belfast, Northern Ireland, UK and 3Royal Liverpool University Hospital and School of Infection and Host Defense, Liverpool University, Liverpool, UK Natural killer (NK) cells are lymphocytes of the innate immune system. In humans, NK cell activities are partly controlled by the diverse killer immunoglobulin-like receptor (KIR) gene family. The importance of NK cells in both immunity to infection and reproduction makes KIR strong candidates for genes undergoing dynamic evolution in the human genome. Using high- resolution allelic typing, we investigated the potential role of natural selection in the diversification of KIR in the Irish population. Higher diversity than expected is observed at several loci, consistent with a history of balancing selection acting to maintain several allelic variants at high frequency in the population. KIR diversity is enhanced further at the haplotype level with functional polymorphisms at KIR2DL4, KIR3DL1 and KIR2DS4 defining nine ‘core’ haplotypes. Analysis of these core haplotypes in combination with human leukocyte antigen (HLA) class I ligands revealed several nonrandom associations. In particular, the KIR:HLA association for the core haplotype defined by KIR3DL1*01502 was female specific and a likely consequence of negative selection acting against KIR3DL1*01502 on an HLA-C1/C1 background. Many of the associations between KIR and HLA in the Irish differ from those previously reported, which argues against universal selective pressures for specific KIR:HLA combinations in diverse human populations. Genes and Immunity (2010) 11, 467–478; doi:10.1038/gene.2010.9; published online 4 March 2010 Keywords: NK cells; killer cell immunoglobulin-like receptors; evolution; KIR haplotypes; HLA; natural selection Introduction infections. This system is also considered important during pregnancy when NK cells interact with fetal and To ensure the survival of a species, individuals within trophoblast cells expressing HLA class I to promote populations must possess genetic characteristics, which vascular remodeling and placentation.6–9 KIR are highly enable them to survive infectious disease, reproduce polymorphic and individuals vary in the type and and pass on their genes.1 Natural killer (NK) cells have number of KIR genes they inherit.10 Two broad classifica- been shown to be key immune effector cells in the fight tions of KIR haplotypes exist: ‘A’ haplotypes are against pathogen but they have also been shown to have restricted in terms of the number of genes they possess important roles during pregnancy.2,3 These contrasting and primarily encode for inhibitory receptors (KIR2DL1, activities involve the killer cell immunoglobulin-like KIR2DL3, KIR3DL1, KIR3DL2, KIR2DL4 and the activat- receptors (KIR) and human leukocyte antigen (HLA) ing gene, KIR2DS4). In contrast, ‘B’ haplotypes have a receptor:ligand system. KIR are a family of receptors higher gene content (ranges from 7–16 genes) and encoded on human chromosome 19 that are expressed on although they have genes encoding for inhibitory the surface of NK cells.4,5 They enable NK cells to receptors (including the characteristic KIR2DL5 gene), recognize and respond to HLA class I downregulation on they also have additional activating genes including target cells, an important hallmark of many viral KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 and KIR3DS1.11,12 NK cell function is highly dependent on the type of KIR and HLA that individuals inherit, and a range of Correspondence: Dr CM Gardiner, School of Biochemistry and compound genotypes conferring different NK cell Immunology, Trinity College, Dublin 2, Ireland. responsiveness phenotypes have been defined.13–15 The E-mail: [email protected] dual role of KIR:HLA genes in immunity to infection and 4 Current address: Institute of Agri-Food & Land Use, Queen’s reproduction makes them good candidates for genes University, David Keir Building, Stranmillis Road, Belfast BT9 5AG, Northern Ireland. undergoing natural selection and coevolution in the Received 28 September 2009; revised 2 December 2009; accepted 6 human genome. Characteristics that promote survival January 2010; published online 4 March 2010 against pathogen and successful reproduction are likely KIR and HLA genes are coevolving KJ Guinan et al 468 to be increased in frequency in humans, whereas genes that hinder these processes may be reduced in frequency. Analysis is complex as KIR and HLA genes are inherited on different chromosomes, known interactions are epistatic and not all functional interactions have been defined. However, there is evidence for coevolution between these genes as a positive association between the presence of inhibitory KIR and their HLA ligands, and a strong negative association between activating KIR and their HLA ligands is observed globally across human populations.16 Furthermore, we have previously found evidence that KIR and HLA class I genes are coevolving within Europe and have shown a balance between inhibitory and activating KIR repertoires, and their ligands, in different regions of Europe.17 Supporting the view that these genes are coevolving, a gender bias in terms of nonrandom associations between KIR core haplotypes and HLA class I has been found in the Japanese population.18 Of particular interest was the finding that several associations between KIR and HLA genes were limited to females supporting the view that reproduction is a strong selective pressure acting on KIR genes.1,7,18 It is not known whether the particular combinations of KIR and HLA found in Japanese women reflects a universal mechanism to promote reproductive success and/or resistance to pathogen within the human species or whether it is a consequence of more local Figure 1 Balancing selection drives high KIR diversity in the Irish environmental and genetic selective pressures. To test the population. (a) Donors were typed to the allele level for five hypothesis that there is a universal selective pressure polymorphic KIR (sample numbers indicated separately for each locus) and the frequencies (F) of each are shown. Ambiguous allele operating to promote particular KIR and HLA combina- typing is indicated. (b) Diversity at these five polymorphic KIR gene tions in humans, potentially in a gender-specific manner, loci was assessed using the Ewens Watterson test. The black line we performed high-resolution allelic analysis of KIR and indicates heterozygosity expected under evolutionary conditions of HLA class I genes in the Irish population and investi- neutrality. Values above the black line indicate deviation from gated their coevolution with respect to known functional neutrality consistent with balancing selection, whereas deviation interactions. below the line reflects processes of purifying selection. Significant deviation from neutrality is indicated by *P-value o0.05, **P-value o0.01, ***P-value o0.0001. Results To investigate the role of natural selection acting on KIR indicated by blue-rimmed boxes (Po0.05). A striking genes in a genetically homogenous population, Irish relationship is seen when we look at LD between alleles donors (n ¼ 240) were typed to the allele level for of KIR2DL4 and KIR3DL1. For a given allele of KIR3DL1 five polymorphic loci (KIR2DL3, KIR2DL4, KIR3DL1, (with the exception of KIR3DL1*007/*020 that is KIR2DS4 and KIR3DL2 loci). Diversity at these loci was found with two alleles of KIR2DL4), there is only ever assessed using the BOTTLENECK program,19 which positive LD with a single allele at the KIR2DL4 locus, for compares heterozygosity at an individual locus to that example, KIR3DL1*00101 is only found in strong positive expected under neutral conditions. Each KIR locus LD with KIR2DL4*00801. Alleles of KIR2DL4 are exhibits heterozygosity greater than expected and, in found in positive LD with a restricted and generally particular, this is statistically significant for KIR2DL4 nonoverlapping subset of KIR3DL1 alleles, for example, (Po0.0001), KIR3DL1 (Po0.01) and KIR2DS4 (Po0.05) KIR2DL4*00801 is found in strong LD with both loci (Figure 1). A higher level of heterozygosity than KIR3DL1*00101 and KIR3DL1*009 and neither of these expected is consistent with a history of balancing KIR3DL1 alleles are found in positive LD with any other selection acting to maintain several alleles at high KIR2DL4 allele. Similarly, alleles of KIR2DS4 are found frequency in the population. No evidence of purifying in strong LD with alleles of KIR2DL4 giving unique LD selection on any single allele was detected. associations between these genes. In combination with We next analyzed the cohort for evidence of linkage KIR2DL4/KIR3DL1 data, this predicts a three-gene core disequilibrium (LD) between alleles of KIR genes using haplotype defined by alleles of KIR2DL4–KIR3DL1– the recently developed MIDAS program.20 This involved KIR2DS4. Indeed, LD analysis of individual KIR3DL1 a systematic pairwise comparison of the frequency of alleles shows that they are almost uniquely associated each unique combination
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