Immunogenetics of HLA-B: SNP, allele, and haplotype diversity in populations from different continents and ancestry backgrounds

HLA-B is among the most variable gene in the human genome. This gene encodes a key molecule for antigen presentation to CD8+ T lymphocytes and NK cell modulation. Despite the myriad of studies evaluating its coding region (with an emphasis on exons 2 and 3), few studies evaluated introns and regulatory sequences in real population samples. Thus, HLA-B variability is probably underestimated. We applied a bioinformatics pipeline tailored for HLA genes on 5347 samples from 80 different populations, which includes more than 1000 admixed Brazilians, to evaluate the HLA-B variability (SNPs, indels, MNPs, alleles, and haplotypes) in exons, introns, and regulatory regions. We observed 610 variable sites throughout HLA-B; the most frequent variants are shared worldwide. However, the haplotype distribution is geographically structured. We detected 920 full-length haplotypes (exons, introns, and untranslated regions) encoding 239 different protein sequences. HLA-B gene diversity is higher in admixed populations and Europeans while lower in African ancestry individuals. Each HLA-B allele group is associated with specific promoter sequences. This HLA-B variation resource may improve HLA imputation accuracy and disease-association studies and provide evolutionary insights regarding HLA-B genetic diversity in human populations.

Automated summary

HLA-B is a highly variable gene in the human genome, encoding a key molecule for antigen presentation and immune cell modulation. However, previous studies focused mainly on coding regions, and the variability of introns and regulatory regions remains underexplored. In this study, a bioinformatics pipeline was used to assess HLA-B variability in a large population sample, revealing a high number of variable sites and geographically structured haplotype distribution. The findings suggest that HLA-B gene diversity is influenced by both population admixture and regional differences. This resource can enhance HLA imputation accuracy and advance our understanding of HLA-B genetic diversity in human populations.