HLA class I diversity in outbred north american populations

Our laboratory has been involved in the analysis of the distribution of HLA class I alleles in different populations. We have performed allele level typing of HLA-A, B and C utilizing PCR-SSOP methods with locus and group-specific primers. We have studied subjects from five major outbred groups living in the U.S.A. (African, AFAM; Caucasians, CAU; Asian, ORI; Hispanic, HIS; and Native Americans, NAI) totaling 1332 unrelated subjects. We compared the distribution of alleles and found variable number of alleles with gene frequency (gf) >0.01 in the different populations. AFAM showed the highest number of HLA-A alleles, while the other populations had between 14 and 18 alleles. In HLA-B we observed a similar degree of diversity as HLA-A in AFAM (n=24) and higher number of alleles in the other groups (23 to 30). HLA-C showed less diversity (15 to 18 alleles). The heterozygosity values reflect the similarity of the allelic frequencies of the alleles. We observed higher levels of heterozygosity for HLA-B (ranging 0.966 to 0.944) compared to HLA-A to and C in all populations (ranging from 0.912 to 0.877) with the exception of AFAM in which the heterozygosity frequency for HLA-A was of similar magnitude (0.938). We estimated haplotype frequencies and linkage diseqilibrium values, and we observed many B/C associations and smaller number of A/B associations. In general, the B/C associations had relative delta values (D') >0.75 while the A/B pairs had D'<0.40. The significant B/C associations combined more than 0.75 of the gf while A/B associations covered less than 0.40 of the gf. We observed a large number of ethnic specific alleles and haplotypes, 20 of the 24 AFAM A/B haplotypes were uniquely observed in this group. This estimation suggests that at least 64% of the AFAM subjects will not find an HLA-A, B identical subject in non-African subjects. Similar observations were made for other ethnic groups when genetic distances (GD) were measured. GD measured by HLA-A allele distributions showed that CAU are closer to HIS and NAI (0.30 and 0.33) followed by AFAM (0.47) and are distant from ORI (0.55). HLA-B distributions showed similar trends with ORI being the most distant from the other populations (range 0.56 to 0.70) while the other populations were closer among each other (ranging from 0.36 to 0.52). We observed a high degree of HLA class I diversity in different populations this was much more apparent with allele level testing. This degree of diversity indicates that finding HLA allele level matches from unrelated donors and recipients is difficult across racial disparity. The diversity is probably the result of a combined effect between population migrations, admixture and the evolutionary forces (balancing selection and heterozygous advantage) that may have acted on the MHC of the population founders.