HLA class I haplotype diversity is consistent with selection for frequent existing haplotypes.

Idan Alter,Martin Maiers,Yoram Louzoun,Stephanie Fingerson,Loren Gragert,Franz J Weissing

doi:10.1371/journal.pcbi.1005693

Abstract

The major histocompatibility complex (MHC) contains the most polymorphic genetic system in humans, the human leukocyte antigen (HLA) genes of the adaptive immune system. High allelic diversity in HLA is argued to be maintained by balancing selection, such as negative frequency-dependent selection or heterozygote advantage. Selective pressure against immune escape by pathogens can maintain appreciable frequencies of many different HLA alleles. The selection pressures operating on combinations of HLA alleles across loci, or haplotypes, have not been extensively evaluated since the high HLA polymorphism necessitates very large sample sizes, which have not been available until recently. We aimed to evaluate the effect of selection operating at the HLA haplotype level by analyzing HLA A~C~B~DRB1~DQB1 haplotype frequencies derived from over six million individuals genotyped by the National Marrow Donor Program registry. In contrast with alleles, HLA haplotype diversity patterns suggest purifying selection, as certain HLA allele combinations co-occur in high linkage disequilibrium. Linkage disequilibrium is positive (Dij'>0) among frequent haplotypes and negative (Dij'<0) among rare haplotypes. Fitting the haplotype frequency distribution to several population dynamics models, we found that the best fit was obtained when significant positive frequency-dependent selection (FDS) was incorporated. Finally, the Ewens-Watterson test of homozygosity showed excess homozygosity for 5-locus haplotypes within 23 US populations studied, with an average Fnd of 28.43. Haplotype diversity is most consistent with purifying selection for HLA Class I haplotypes (HLA-A, -B, -C), and was not inferred for HLA Class II haplotypes (-DRB1 and—DQB1). We discuss our empirical results in the context of evolutionary theory, exploring potential mechanisms of selection that maintain high linkage disequilibrium in MHC haplotype blocks.

Highlights

Human leukocyte antigen (HLA) genes in the major histocompatibility complex (MHC) on Chromosome 6 provide the core function of antigen presentation for the adaptive immune system
Purifying selection for human leukocyte antigen (HLA) class I haplotypes loci coding for these molecules are found in major histocompatibility complex (MHC) region, the most polymorphic region in the human genome, with over 15,000 HLA alleles observed so far in the world population
New HLA alleles may have an advantage over existing frequent alleles since immune escape mutations in pathogens within a population are maintained primarily in epitopes presented on frequent HLA alleles

Summary

Introduction

Human leukocyte antigen (HLA) genes in the major histocompatibility complex (MHC) on Chromosome 6 provide the core function of antigen presentation for the adaptive immune system. Each HLA allele can present a restricted repertoire of peptides from either self or nonself proteins to T cell receptors. For HLA genes amino acid variation in the antigen recognition domain of HLA proteins determines the repertoire of peptides loaded onto the HLA protein and presented to the T cell receptor. Compared to other genes nonsynonymous variants in HLA genes were proposed to be often advantageous because a novel peptide repertoire may improve control of evolving pathogen strains [7]. Comparing patterns of variation among different genes, HLA has among the highest ratios of nonsynonymous substitutions relative to synonymous substitutions, which is a hallmark of balancing selection (i.e. selection maintaining a larger number of alleles than expected from genetic drift). The Ewens-Watterson test for neutrality shows that observed HLA allele homozygosity is less than expected, another indicator consistent with balancing selection [8]

Objectives

Methods

Results

Discussion

Conclusion