Evidence for Natural Selection on Leukocyte Immunoglobulin-like Receptors for HLA Class I in Northeast Asians

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.

Leukocyte Immunoglobulin-Like Receptors as New Players in Autoimmunity

“…Interestingly, LILRA3 deficiency is, with an allele frequency of 71% in Japan as well as in other populations from Northeast Asia, very common. LILRA3 alleles were found to be in strong linkage disequilibrium with LILRB2 alleles, which were associated with a low expression of LILRB2, and there is evidence of a positive selection acting on both loci in Northeast Asians [11].…”

Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations

“…Moreover, LILRB2 alleles are in linkage disequilibrium with LILRA3 deletion polymorphism, and the region shows evidence of positive selection. 12 Similar to LILRB1, LILRB2 recognizes a broad range of HLA class I alleles as ligands. 18,22,24,35 However, in contrast to LILRB1, LILRB2 recognizes not only β2 m-free forms of HLA class I but also heavy chain dimers including HLA-B27 and HLA-G, more strongly than classical HLA class I.…”

“…34,36,37 LILRB2 SNPs are markedly differentiated between East Asians, including Japanese and Chinese, and non-East Asians, including Europeans and Africans. 12 The LILRB2 alleles commonly found in East Asians are significantly associated with low levels of cell surface expression in monocytes. Moreover, LILRB2 alleles are in linkage disequilibrium with LILRA3 deletion polymorphism, and the region shows evidence of positive selection.…”

“…LILRA3 is deficient in more than half of East Asians, indicating that LILRA3 is not essential for survival. 12 However, LILRA3 deletion polymorphism has been reported to be associated with several autoimmune diseases. First, LILRA3 deficiency is a risk factor for multiple sclerosis in the German and Spanish populations but not in the Polish population.…”

“…10,11 East Asian populations have high frequency (up to 84%) of the LILRA3-deleted allele, compared with that in European (17%) and African (7%) populations. 12 In addition, nonfunctional alleles containing premature stop codons have been detected in East Asians. 13 These nonfunctional alleles are estimated to have been maintained for a long time in humans, suggesting that balancing selection has been acting on this locus.…”