HLA-DR and -DQ gene polymorphism in West Africans is twice as extensive as in north European Caucasians: evolutionary implications.

Abstract

The HLA genes are the most polymorphic coding loci known in humans. DRB-DQA-DQB gene polymorphism was investigated by Taq I restriction fragment length polymorphism analysis in more than 700 West Africans and found to be almost twice as extensive in West Africans as in North European Caucasians. This finding indicates that Africans comprise the oldest and genetically most diverse human population and supports the hypothesis of the occurrence of a population bottleneck in the emergence of the White race. As in Caucasians, less than one-third of possible cis-encoded DQA-DQB combinations were encountered, indicating constraints on the pairing of DQ a and P polypeptides. Heterozygote advantage (i.e., positive selection) was found for DRB, DQA, and DQB alleles as well as for DQA-DQB combinations. However, in West Africans as well as in North Europeans the observed frequencies of DRB-DQA-DQB homozygotes were close to neutrality expectations. Although the hypothesis that HLA polymorphism is maintained by parasite-driven overdominant selection is attractive, there is little evidence to support that view. We propose instead that one of the forces maintaining a low frequency of HLA homozygotes might be a decreased likelihood of potentially autoreactive T-cell clones escaping thymic selection in HLA heterozygotes. This would be consistent with the central role of HLA molecules as self/nonself discriminators.Most expressed HLA genes exhibit a remarkable degree of allelic polymorphism, which derives from sequence differences predominantly localized to discrete hypervariable Tegions in the amino-terminal -domains of the molecule. HLA variability influences both self-adjustment of the T-cell repertoire during thymic maturation and immune responsiveness of an individual to antigenic peptides.Major histocompatibility complex (MHC) polymorphism has several unique features: most loci have7 many alleles, no allele dominates in frequency, and alleles differ by many amino acid substitutions. Two hypotheses, retention of-ancestral polymorphisms and hypermutational diversification, have dominated speculations on the evolutionary origin of MHC diversity. The trans-species evolution theory (1)-i.e., that most major MHC allelic types diverged prior to the origin of the species in which they are found-has been supported by sequence analysis of rodent and primate MHC genes (2-5). The rate of amino acid-altering substitutions exceeds that of silent substitutions in codons of contact amino acids in the antigen-binding site of MHC class I and class II molecules, indicating that selection operates directly on the antigen-binding site (6-8). The high degree of-polymorphism, long persistence of alleles, low frequency of homozygotes, and high rate of replacement substitutions can best be explained by overdominant selection. However, the evolutionary force(s) exerting such selection pressure remain-unclear.Restriction fragment length polymorphism (RFLP) analysis of HLA class II genes, especially DR and DQ, has been developed into a powerful...

Effects of Antenatal and Postnatal Environments on CD4 T-Cell Responses toMycobacterium bovisBCG in Healthy Infants in The Gambia

“…Differences in the HLA repertoires of the Fula, Wolof, and Mandinka in The Gambia have been found (35), and inheritance of class II HLA genes has been associated with the heritability of the IFN-␥ response to PPD (32). However, it has not been established whether the alleles that influenced responses to PPD were the same as those that varied between ethnic groups or whether Gambian Mandinka are more genetically similar to the Mandinga of Guinea-Bissau than to sympatric groups in The Gambia.…”

Extensive genetic diversity in the HLA class II region of Africans, with a focally predominant allele, DRB1*1304.

“…The samples from Malawi included healthy children and those attending hospital with malaria. The European frequencies used for comparison were reported by Cullen et al (20) from Northern Ireland; they are similar to those of other northern European populations (21). RFLP Analysis.…”

Distribution Analysis of HLA-DRB1*1501, -DQA1*0102, -DQB1*0602, -DRB5*01, -A*0301 Alleles and Haplotypes in Normal Population of Khuzestan Province

“…Also, HLA Typing may aid the understanding of how gene conversions, recombinations, mutations as well as some random mechanisms like genetic drifts and founder effects have impacted on the present genetic background of various populations. Investigation of the HLA-DRB, HLA-DQA and HLA-DQB gene variations has represented that Africans comprise the oldest and genetically the most diverse human population [3]. It has also been shown that the genetic distance between Asians and Africans or of that between Europeans and Africans are much more than that between Europeans and Asians [4].…”