Evolutionary analysis of classical HLA class I and II genes suggests that recent positive selection acted on DPB1*04:01 in Japanese population

PLoS One. 2012;7(10):e46806. doi: 10.1371/journal.pone.0046806. Epub 2012 Oct 3.


The human leukocyte antigen (HLA) genes exhibit the highest degree of polymorphism in the human genome. This high degree of variation at classical HLA class I and class II loci has been maintained by balancing selection for a long evolutionary time. However, little is known about recent positive selection acting on specific HLA alleles in a local population. To detect the signature of recent positive selection, we genotyped six HLA loci, HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese subjects, and then assessed the haplotype homozygosity (HH) of each HLA allele. There were 120 HLA alleles across the six loci. Among the 80 HLA alleles with frequencies of more than 1%, DPB1*04∶01, which had a frequency of 6.1%, showed exceptionally high HH (0.53). This finding raises the possibility that recent positive selection has acted on DPB1*04∶01. The DPB1*04∶01 allele, which was present in the most common 6-locus HLA haplotype (4.4%), A*33∶03-C*14∶03-B*44∶03-DRB1*13∶02-DQB1*06∶04-DPB1*04∶01, seems to have flowed from the Korean peninsula to the Japanese archipelago in the Yayoi period. A stochastic simulation approach indicated that the strong linkage disequilibrium between DQB1*06∶04 and DPB1*04∶01 observed in Japanese cannot be explained without positive selection favoring DPB1*04∶01. The selection coefficient of DPB1*04∶01 was estimated as 0.041 (95% credible interval 0.021-0.077). Our results suggest that DPB1*04∶01 has recently undergone strong positive selection in Japanese population.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian Continental Ancestry Group
  • Gene Frequency / genetics
  • Genotype
  • HLA-A Antigens / genetics
  • HLA-B Antigens / genetics
  • HLA-C Antigens / genetics
  • HLA-DP beta-Chains / genetics
  • HLA-DQ beta-Chains / genetics
  • Haplotypes
  • Histocompatibility Antigens Class I / genetics*
  • Histocompatibility Antigens Class II / genetics*
  • Humans
  • Selection, Genetic / genetics*


  • HLA-A Antigens
  • HLA-B Antigens
  • HLA-C Antigens
  • HLA-DP beta-Chains
  • HLA-DPB1 antigen
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Histocompatibility Antigens Class I
  • Histocompatibility Antigens Class II

Grant support

This work was supported by National Bioscience Database Center (NBDC) of Japan Science and Technology Agency (JST), by KAKENHI (22133008) Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and by KAKENHI (23133502) Grant-in-Aid for Scientific Research on Innovative Areas. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.