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

Area of Science:

• Immunogenetics
• Evolutionary biology
• Population genetics

Background:

• The Major Histocompatibility Complex (MHC) harbors highly polymorphic human leukocyte antigen (HLA) genes, crucial for the adaptive immune system.
• High allelic diversity in HLA is traditionally attributed to balancing selection mechanisms.
• Selection pressures on combinations of HLA alleles (haplotypes) remain less understood due to the need for large sample sizes.

Purpose of the Study:

• To investigate the impact of selection acting at the HLA haplotype level.
• To analyze HLA-A~C~B~DRB1~DQB1 haplotype frequencies in a large population dataset.
• To evaluate evolutionary models explaining observed haplotype diversity patterns.

Main Methods:

• Analysis of HLA haplotype frequencies from over six million genotyped individuals.
• Assessment of linkage disequilibrium patterns among HLA alleles.
• Fitting haplotype frequency distributions to population dynamics models, including frequency-dependent selection.
• Application of the Ewens-Watterson test of homozygosity.

Main Results:

• HLA haplotype diversity patterns indicate purifying selection, contrasting with allele-level balancing selection.
• Significant positive frequency-dependent selection best explained the observed haplotype frequency distribution.
• Excess homozygosity was detected for 5-locus haplotypes across 23 US populations.
• Purifying selection was inferred for HLA Class I haplotypes but not for HLA Class II haplotypes.

Conclusions:

• HLA haplotype structure is shaped by purifying selection, maintaining high linkage disequilibrium in specific blocks.
• Frequency-dependent selection plays a role in shaping HLA haplotype frequencies.
• Distinct evolutionary pressures may operate on HLA Class I versus Class II haplotypes.