HLA class I allele distributions in six Pacific/Asian populations: evidence of selection at the HLA-A locus.

Abstract

The distributions of HLA-A alleles in six Pacific/Asian populations, Malay, Papua New Guinea (PNG) Highlands, two Indonesian groups, and two PNG Lowland groups, as well as the distribution of the HLA-B alleles in the PNG Highlands population, were determined using polymerase chain reaction (PCR) immobilized sequence-specific oligonucleotide (SSO) probe typing methods. The allele frequency distributions at the HLA class II loci, DRB1, DQB1 and DPB1 were also determined by PCR/SSO methods in an additional study of the same populations. In most of these populations, the HLA-A*2402 allele was the most frequent, attaining a frequency of 0.78 in the PNG Highlands. A*1101 was the next most frequent allele, followed in frequency by the *3401 allele. The HLA-B*1506, *4001, *5601 and *5602 alleles comprised 73% of the allele diversity at the B-locus in the PNG Highlands. Two previously unreported HLA-A alleles were identified in Indonesians and Malays, based on novel probe reactivity patterns. Cloning and sequencing identified these as A*1104 and *2410. Sequence comparisons show that these new alleles differ at codon 187 from their putative parental alleles (*1101 and *2403) by dinucleotide changes in the first two codon positions. These changes involve a Thr to Arg (CG to AC) and an Arg to Thr substitution (AC to CG) at position 187; residues at this position participate in pocket A of the peptide binding groove. Comparison of the HLA-A allele frequency distributions indicate that Malays are the most diverse (heterozygosity (h)=0.88) and the PNG Highlanders are, by far, the least diverse (h=0.37) of the groups studied. However, the diversity of B-locus alleles in the PNG Highlanders (h=0.91) was greater than that observed at the A-locus of any of the populations reported here. The remarkably high allele frequency of A*2402 in the PNG Highlands could reflect founder effects and population bottlenecks, genetic drift, or positive directional selection. The distribution of the HLA-B locus alleles and class II alleles, as well as mtDNA sequence data in the PNG Highlands indicates a reasonably high level of diversity at other loci, arguing that the high frequency of A*2402 cannot be attributed entirely to founder effects, bottlenecks, or drift and suggests the operation of positive selection for the A*2402 allele in this population.