Genetic Diversity and Haplotype Architecture of Non‐Classical HLA Class I Genes in the Japanese Population

ABSTRACT

The non‐classical Class I genes (HLA‐E, HLA‐F and HLA‐G) show limited protein‐level diversity; however, full‐length analyses that include regulatory and noncoding regions have not been sufficiently performed in East Asian populations. We designed new primers for long‐range PCR and conducted PacBio SMRT sequencing to generate full‐length gene sequences of HLA‐E, HLA‐F and HLA‐G, including 5′ and 3′ untranslated regions (UTRs) as well as coding and intronic regions in 531 healthy Japanese individuals. These data enabled the full phasing of HLA‐E, HLA‐F and HLA‐G, including upstream and downstream variants, at four‐field resolution. We identified 24 HLA‐E alleles, 30 HLA‐F alleles and 19 HLA‐G alleles, including a total of 36 novel (10 HLA‐E, 19 HLA‐F and 7 HLA‐G) and 16 extended alleles (13 HLA‐E, 1 HLA‐F and 2 HLA‐G). Protein‐level diversity for HLA‐E was limited, with E*01:03 and E*01:01 predominating. For HLA‐F, despite the predominance of F*01:01 (96.7%), noncoding diversity at four‐field resolution was abundant; the expression‐linked rs2523405‐T allele phased with F*01:01:02 and F*01:01:06 , as well as with a subset of F*01:01:01 sub alleles. For HLA‐G, consistent with previous reports, four‐field resolution alleles and UTR variants formed fully co‐segregating haplotypes. Linkage disequilibrium (LD) analysis at four‐field resolution showed no LD between HLA‐E and either HLA‐F or HLA‐G, whereas moderate LD was observed between HLA‐F and HLA‐G; the strongest signal was driven by F*01:01:02:09 , which forms a haplotype with G*01:01:03:03 . In summary, full‐gene long‐read sequencing clarified allele frequencies of non‐classical Class I genes in the Japanese population, delineated phasing in regulatory regions and refined the LD structure between HLA‐F and HLA‐G by resolving four‐field haplotypes. These data constitute an important reference for immunogenetic research, transplantation and disease‐association studies in the Japanese population.