Possible KIR-driven genetic pressure on the genesis and maintenance of specific HLA-A,B haplotypes as functional genetic blocks

Capittini, Cristina; Tinelli, Carmine; Guarene, M.; Pasi, Annamaria; Badulli, C.; Sbarsi, Ilaria; Garlaschelli, F.; Cremaschi, A. L.; Pizzochero, C.; Monti, Claudio; Salvaneschi, L.; Martinetti, Miryam

doi:10.1038/gene.2012.14

Cited by 16 publications

(20 citation statements)

References 26 publications

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“…KIR3DL1 recognizes HLA-B and HLA-A molecules with the Bw4 epitope [8] and it has been suggested that KIR3DS1 also binds the Bw4 epitope [9], [10]. Although HLA-B epitopes are currently considered the most important KIR3DL1/S1 ligands, we recently suggested that both HLA-A and B allotypes may be equally important for NK function [11], which corroborates the suggestion about HLA-A and HLA-B having compensatory function in the engagement of KIR receptors and being a KIR-driven functional genetic block [12].…”

Section: Introductionsupporting

confidence: 85%

KIR Gene Content in Amerindians Indicates Influence of Demographic Factors

et al. 2013

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Although the KIR gene content polymorphism has been studied worldwide, only a few isolated or Amerindian populations have been analyzed. This extremely diverse gene family codifies receptors that are expressed mainly in NK cells and bind HLA class I molecules. KIR-HLA combinations have been associated to several diseases and population studies are important to comprehend their evolution and their role in immunity. Here we analyzed, by PCR-SSP (specific sequencing priming), 327 individuals from four isolated groups of two of the most important Brazilian Amerindian populations: Kaingang and Guarani. The pattern of KIR diversity among these and other ten Amerindian populations disclosed a wide range of variation for both KIR haplotypes and gene frequencies, indicating that demographic factors, such as bottleneck and founder effects, were the most important evolutionary factors in shaping the KIR polymorphism in these populations.

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Section: Introductionsupporting

confidence: 85%

KIR Gene Content in Amerindians Indicates Influence of Demographic Factors

et al. 2013

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“…We have previously suggested that although KIR2DL2 313 binds HLA-C ligands with higher affinity than KIR2DL3 [55], relax- Recently, we suggested that both HLA-A and HLA-B could be 342 equally important for KIR recognition [41]. In a remarkable study, 343 Capittini et al [63] …”

mentioning

confidence: 95%

“…The KIR have evolved 61 rapidly, facilitated by unequal crossing over between the several 62 paralogous KIR genes [6,8]. Although many studies have described 63 KIR diversity in worldwide populations, only a few genetically iso- 64 lated populations have been studied, and even fewer have ana- 65 lyzed KIR in the context of their well-established ligands, the 66 Genetic distances were estimated based on the frequencies of 106 KIR gene-content genotypes. The estimation was performed 107 according to Nei's method [28] using PHYLIP-version 3.6 [29].…”

mentioning

confidence: 99%

A deep look at KIR–HLA in Amerindians: Comprehensive meta-analysis reveals limited diversity of KIR haplotypes

2015

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“…Furthermore, in humans, HLAs interact directly with a second family of immune system genes: Killer-cell Ig-like receptors (KIRs). KIRs display a striking haplotypic structure (21); particular KIR/HLA genotypes have been associated with different infectious disease outcomes (22,23), and a direct effect of KIR/HLA coevolution on HLA haplotypes has recently been suggested (24).…”

Section: Future Directionsmentioning

confidence: 99%

Pathogen selection drives nonoverlapping associations between HLA loci

Penman

Ashby

Buckee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pathogen-mediated selection is commonly invoked as an explanation for the exceptional polymorphism of the HLA gene cluster, but its role in generating and maintaining linkage disequilibrium between HLA loci is unclear. Here we show that pathogenmediated selection can promote nonrandom associations between HLA loci. These associations may be distinguished from linkage disequilibrium generated by other population genetic processes by virtue of being nonoverlapping as well as nonrandom. Within our framework, immune selection forces the pathogen population to exist as a set of antigenically discrete strains; this then drives nonoverlapping associations between the HLA loci through which recognition of these antigens is mediated. We demonstrate that this signature of pathogen-driven selection can be observed in existing data, and propose that analyses of HLA population structure can be combined with laboratory studies to help us uncover the functional relationships between HLA alleles. In a wider coevolutionary context, our framework also shows that the inclusion of memory immunity can lead to robust cyclical dynamics across a range of host-pathogen systems.infectious disease | major histocompatibility complex | mathematical model | human evolution | population genetics H LAs, found on the surface of all nucleated cells, present pathogen peptides to T lymphocytes and are thus a keystone of adaptive immunity. Demonstrable associations of particular HLA alleles with resistance or susceptibility to severe disease (1, 2) underscore the importance of their role in protection against death from infection. The genes encoding HLAs are found in the 3.6-Mb-long MHC on chromosome 6 and are distinguished by their exceptional polymorphism (3), which is likely the result of selection from pathogens (4-6) Despite this enormous diversity, most human populations are dominated by a relatively small number of combinations of the alleles present at the class I HLA (A, B, C) and the principal class II HLA (DP, DQ, and DR) loci (7-12). Here we present a coevolutionary model demonstrating that pathogen selection can drive such long-term, long-range associations between HLAs. We show that this mechanistic process can be distinguished from other evolutionary effects by virtue of generating a higher degree of nonoverlap between HLA repertoires than might be expected under founder effects or hitchhiking.A Multilocus Model for Host-Pathogen Coevolution with Allele-Specific Adaptive Immunity We first explored the properties of a deterministic epidemiological model (Methods) in which (i) the pathogen population was represented by four potential strains defined by two antigenic loci containing alleles (a, b) and (x, y), respectively, and (ii) we defined within a diploid host, alleles (A,B) and (X,Y) at two linked "recognition loci" (i.e., HLA loci), each only capable of responding to the corresponding parasite allele (or epitope) given in lowercase above. We assumed that immunity developed in an allele-specific manner conferring complete protectio...

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Possible KIR-driven genetic pressure on the genesis and maintenance of specific HLA-A,B haplotypes as functional genetic blocks

Cited by 16 publications

References 26 publications

KIR Gene Content in Amerindians Indicates Influence of Demographic Factors

KIR Gene Content in Amerindians Indicates Influence of Demographic Factors

A deep look at KIR–HLA in Amerindians: Comprehensive meta-analysis reveals limited diversity of KIR haplotypes

Pathogen selection drives nonoverlapping associations between HLA loci

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