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. 2008 May;82(5):1075-83.
doi: 10.1016/j.ajhg.2008.03.012. Epub 2008 Apr 24.

Evidence for natural selection on leukocyte immunoglobulin-like receptors for HLA class I in Northeast Asians

Kouyuki Hirayasu  1 , Jun Ohashi, Hidenori Tanaka, Koichi Kashiwase, Atsuko Ogawa, Minoko Takanashi, Masahiro Satake, Guan Jun Jia, Nyam-Osor Chimge, Elena W Sideltseva, Katsushi Tokunaga, Toshio Yabe
Affiliations

Evidence for natural selection on leukocyte immunoglobulin-like receptors for HLA class I in Northeast Asians

Kouyuki Hirayasu et al. Am J Hum Genet. 2008 May.

Abstract

Human leukocyte antigen (HLA) plays a critical role in innate and adaptive immunity and is a well-known example of genes under natural selection. However, the genetic aspect of receptors recognizing HLA molecules has not yet been fully elucidated. Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are a family of HLA class I-recognizing receptors comprising activating and inhibitory forms. We previously reported that the allele frequency of the 6.7 kb LILRA3 deletion is extremely high (71%) in the Japanese population, and we identified premature termination codon (PTC)-containing alleles. In this study, we observed a wide distribution of the high deletion frequency in Northeast Asians (84% in Korean Chinese, 79% in Man Chinese, 56% in Mongolian, and 76% in Buryat populations). Genotyping of the four HapMap populations revealed that LILRA3 alleles were in strong linkage disequilibrium with LILRB2 alleles in Northeast Asians. In addition, PTC-containing LILRA3 alleles were detected in Northeast Asians but not in non-Northeast Asians. Furthermore, flow-cytometric analysis revealed that the LILRB2 allele frequent in Northeast Asians was significantly associated with low levels of expression. F(ST) and extended-haplotype-homozygosity analysis for the HapMap populations provided evidence of positive selection acting on the LILRA3 and LILRB2 loci. Taken together, our results suggest that both the nonfunctional LILRA3 alleles and the low-expressing LILRB2 alleles identified in our study have increased in Northeast Asians because of natural selection. Our findings, therefore, lead us to speculate that not only HLA class I ligands but also their receptors might be sensitive to the local environment.

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Figures

Figure 1
Figure 1
Geographical Distribution of LILRA3 Allele Frequencies The pie chart displays the allele frequencies of populations in Table 2. Each number refers to the populations shown in Table 2.
Figure 2
Figure 2
Schematic Diagram of the Four SNPs Identified in the LILRB2 Gene Each numbered block indicates an exon. White and black blocks show the UTR and the coding region, respectively. The pie chart displays the allele frequencies of the SNPs shown in Table 3. SS and TM stand for “signal sequence” and “transmembrane,” respectively.
Figure 3
Figure 3
LD Analysis of LILRA3, LILRB2, and Adjacent Genes in JPT+CHB The numbers within each square indicate the D′ values.
Figure 4
Figure 4
Association of LILRB2 c.59GG, GA, and AA Genotypes with Cell-Surface Expression (A) Vertical and horizontal axes indicate median fluorescence intensity (MFI) and LILRB2 genotypes (c.59GG, GA, AA), respectively. p values were calculated with the Mann-Whitney U test. (B) Representative flow-cytometry histogram of c.59GG (left) and c.59AA (right) genotypes. Vertical and horizontal axes show cell number and fluorescence intensity, respectively. “Open” and “Closed” histograms illustrate staining with an isotype-matched control and an anti-LILRB2, respectively.
Figure 5
Figure 5
FST Analysis of LILRA3 and LILRB2 Empirical distributions of FST between (A) JPT+CHB and CEU and (B) JPT+CHB and YRI, for all of the SNPs on chromosome 19 in the HapMap data, are shown. Vertical and horizontal axes indicate the number of polymorphisms and FST values, respectively. The 95th and 99th percentiles are shown. The LILRB2 SNP in the signal sequence (c.59A→G) is indicated as a representative of the four SNPs shown in Table 3.
Figure 6
Figure 6
EHH Analysis of LILRA3 and LILRB2 Core Haplotypes REHH versus distance (cM) plots of (A) LILRA3 and (B) LILRB2 core haplotypes are shown. Deep red line indicates the tested core haplotype. Empirical distributions of the REHH values in the same frequency bin are displayed in (C) (LILRA3 bin; 0.7–0.75) and (D) (LILRB2 bin; 0.80–0.85). The 95th and 99th percentiles are indicated.
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