Genetic variability, molecular evolution, and geographic diversity of HLA-B27

HLA-B27 represents a family of 23 closely related alleles (B*2701-23) that differ at 24 amino acid positions. The pattern of polymorphisms of B27 was studied, with special reference to synonymous (Ks) and nonsynonymous (Ka) d ivergence among alleles. B27 alleles are characterized by the enhanced rate of nonsynonymous nucleotide substitution in the peptide-binding region (PB R). The percentage of substitutions between each of the B27 pairs ranges fr om 0.2%-3% in exons 2-3 to 1.8%-20.1% in the PBR. A phylogenetic analysis o f all B27 alleles is described in order to identify subtypes with a common evolutionary history. These results, together with the phylogenetic trees o btained from the comparison between exons 2-3 and PBR indicate that polymor phism of B27 is selectively maintained. Most of the differences are cluster ed in the C/F pocket affecting the specific binding of antigenic peptides. Gene conversion and point mutation are the most important mechanisms respon sible for B27 diversification. The interaction of selection, genetic drift, and recombination events is important for generating polymorphism at B27 a lleles. We analyzed a large extended B27 positive population from different parts of the world. Our results indicate that B27 subtypes differ in their ethnic distribution, which may be the result of different genetic and geog raphical origins. Different factors such as genetic drift, bottleneck effec t, and admixture among populations could contribute to the genetic constitu tion of B27. The striking correlation between the structural features of B2 7 and the ethnic distribution of these subtypes suggests a model of strong directional evolution, in which the subtypes could have arisen from B*2705. Human Immunology 62. 1042-1050 (2001). (C) American Society for Histocompa tibility and Immunogenetics, 2001. Published by Elsevier Science Inc.