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.

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

“…This is consistent with the lack of LD between LILRA3 deletion and KIR genes observed by Norman et al 47 in British Caucasoids. Furthermore, stratification for the presence or absence of the LILRA3 deletion showed again no significant difference between patients and controls in the frequency of any KIR gene or genotype after In the complete LILRA3 form, FP1 and RP produce a 150-bp amplicon, whereas FP2 anneals with the DNA, but does not yield a product due to excessive amplicon length (B7 kb).…”

Receptor systems controlling natural killer cell function are genetically stratified in Europe

“…14,17,18,20 However, it is very difficult in this type of analysis to distinguish between processes of natural selection and demographic history. Many of the gradients observed for KIR and HLA in this study are similar to the distribution of Y chromosome and mitochondrial DNA markers in Europe that have been attributed to population movements and founder effects.…”

“…The opposing functions of activatory and inhibitory KIR is believed to reflect underlying processes of balancing and positive selection in response to pressures imposed by pathogens and coevolution with their rapidly evolving HLA class I ligands. 14,[17][18][19][20] Evidence also suggests the emergence of KIR to fulfill important roles during pregnancy [21][22][23] in which it has been shown that they influence the role of uterine NK cell in vascular remodeling during fetal trophoblast cell invasion of the deciduas. 24 As a likely consequence of these selective pressures, KIR diversity at the genetic, phenotypic and functional levels is immense.…”

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

“…The reason is that multiple diverse genotypes were detected in few individuals23, 26, 52 and the only plausible explanation was a highly heterogeneous genetic system with multiple common variants. These early studies therefore provided the first evidence that KIR may be subject to natural selection that maintains high diversity, just like it does for HLA 19, 53. The Yucpa population from Venezuela has low genomic diversity as a consequence of serial founder effects 54.…”

“…The A haplotype can be divided into two types depending on whether the KIR 2 DS 4 gene is full‐length ( KIR 2 DS 4 ) or carries a frameshift deletion ( KIR 2 DS 4 del ). (b) Diversity has been generated by homologous recombination, particularly at a recombination hotspot (*) centrally sited within the gene cluster,19 which has shuffled the centromeric (cen) and telomeric (tel) parts of the locus encompassing allelic and gene‐content motifs. (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.…”