Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1075-1083, 24 April 2008
doi:10.1016/j.ajhg.2008.03.012
Article
Evidence for Natural Selection on Leukocyte Immunoglobulin-like Receptors for HLA Class I in Northeast Asians
Kouyuki Hirayasu1, 2, Jun Ohashi2, Hidenori Tanaka1, Koichi Kashiwase1, Atsuko Ogawa1, Minoko Takanashi1, Masahiro Satake1, Guan Jun Jia3, Nyam-Osor Chimge4, Elena W. Sideltseva5, Katsushi Tokunaga2 and Toshio Yabe1, 
, 
1 Tokyo Metropolitan Red Cross Blood Center, Tokyo 135-8639, Japan
2 Department of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan
3 Harbin Red Cross Blood Center, Harbin 150010, China
4 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Have, Connecticut 06511, USA
5 International Department of the Irkutsk Science Center, Siberian Branch of Russian Academy of Science, Irkutsk 664033, Russia
Corresponding authorAbstract
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. FST 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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