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

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.

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

“…In humans, allocation of lineage II and III genes continued both centromerically and telomerically, and at one moment the group B haplotype was formed by introduction of specific activating KIR. Further diversity in humans is generated by recombination events, and a model has been proposed whereby centromeric and telomeric blocks of A or B haplotypes can be recombined to explain the birth of new ones [32]. Therefore, certain KIR combinations are in strong linkage-disequilibrium on these haplotype blocks [47].…”

“…Where the group B haplotypes are characterized by the presence of one or more of the following genes -KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, and KIR3DS1 -the group A haplotypes are defined by the absence of these genes. Moreover, much of the observed haplotype diversity can be explained by dividing these haplotype groups into centromeric and telomeric parts, whereby new haplotypes may be formed by equal and unequal crossover events between these regions [32].…”

“…Where the group B haplotypes are characterized by the presence of one or more of the following genes -KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5, and KIR3DS1 -the group A haplotypes are defined by the absence of these genes. Moreover, much of the observed haplotype diversity can be explained by dividing these haplotype groups into centromeric and telomeric parts, whereby new haplotypes may be formed by equal and unequal crossover events between these regions [32].With regard to the rhesus macaque, only a few individual animals have been analyzed for their KIR content, since the fulllength KIR transcripts of some unrelated animals have been sequenced [33,34]. The subsequent analyses showed that the KIR system in this macaque species is polygenic and polymorphic, and can encode inhibitory and activating molecules with three extracellular domains.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…(c) Further diversity has been generated through continuing cycles of unequal crossing‐over (non‐allelic homologous recombination), which result in re‐assortment and addition or subtraction of genes in a ‘cut & paste’‐like manner 20, 21. So called fusion genes composed of parts of different KIR genes have been generated by unequal crossover events when the recombination has occurred within genes 21, 22…”

The potential influence of KIR cluster profiles on disease patterns of Canadian Aboriginals and other indigenous peoples of the Americas

“…Centromeric and telomeric influences can also provide another level of complexity. 11,12 Ethnically defined disease burdens have been largely attributed to environmental factors. 13,14 However, epidemiological data on reduced rates of progression to chronic hepatitis C infection in North American Aboriginal people despite similar environmental factors [15][16][17][18] suggest that underlying biological events participate in populationspecific disease outcomes.…”