Evolutionary Analysis of Classical HLA Class I and II Genes Suggests That Recent Positive Selection Acted on DPB1*04∶01 in Japanese Population

Minae Kawashima,Nao Nishida,Jun Ohashi,Katsushi Tokunaga,Henry Harpending

doi:10.1371/journal.pone.0046806

Abstract

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.

Highlights

The crucial immunological function of human leukocyte antigen (HLA) molecules is to present pathogen-derived antigenic peptides to T lymphocytes [1]
To identify the signature of recent positive selection that has acted on specific HLA alleles in a local population, we investigated the allele frequencies and haplotype frequencies at HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DQB1, and HLA-DPB1 in 418 Japanese individuals
The extended haplotype homozygosity (EHH) of DPB1*04:01 was reduced at HLA-DQB1, the decrease in EHH was almost negligible at HLA-DRB1, HLA-B, and HLA-C loci; these findings indicate that, in this haplotype, recombination mainly has occurred between DQB1*06:04 and DPB1*04:01

Summary

Introduction

The crucial immunological function of human leukocyte antigen (HLA) molecules is to present pathogen-derived antigenic peptides to T lymphocytes [1]. A remarkable feature of the classical HLA class I and class II genes is the high degree of polymorphism. Positive selection has been shown as a driving force for the high degree of polymorphism at HLA loci [3,4]. The HLA genes show three remarkable signatures of positive selection: (1) the rate of nonsynonymous (amino acid altering) nucleotide substitution is substantially higher than that of synonymous substitution at antigen-recognition sites [5,6], (2) there are trans-species polymorphisms (i.e., similar alleles are present in multiple species) [7], and (3) there is a significant excess of heterozygosity [8,9]. Balancing selection, including overdominant selection and frequency-dependent selection, can account for these observations [3,4]

Methods

Results

Conclusion