Also, the ratio of silent to replacement substitutions in DPB1 sequences is consistent with selection for heterozygosis.52,53 A possible explanation of these results is that HLA-DPB1 would have retained ancient traces of balancing selection at the DNA level,51 although it presently evolves under neutrality. As for most genetic polymorphisms tested, the highest level of HLA genetic diversity is found within populations rather than between populations: on average,

over several HLA loci, MG 132 estimated genetic variation within populations, between populations within broad continental regions, and between broad continental regions are 89·9%, 4·4% and 5·7%, respectively, when seven regions and five learn more loci (HLA-A,

-B, -C, -DRB1, and -DQB1) are considered46 and are 89·4%, 5·1% and 5·5%, respectively, when five regions and seven loci (HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1) are considered.25 Overall, the average diversity within populations of the classical HLA loci is higher than the value of ∼ 85% often cited for neutral genetic markers22,24 except for HLA-DPB1 (84%),25 which matches other evidence of neutrality (mentioned above) for this locus. Solberg et al. (2008)49 have collected detailed data on the HLA diversity in different populations worldwide (but see also http://www.allelefrequencies.net/). Table 4 lists the four most frequent (FMF) alleles at each of the classical HLA loci in 10 regions of the world, along with the cumulative frequency for those alleles (CAF)

in each region. This table also includes an ‘other’ region (OTH) with admixed populations derived from more than one region. Only a few of the FMF Methane monooxygenase HLA-B alleles (e.g. B*40:02, or *51:01G) are shared across regions. The low CAF of these alleles, which represent 50% or less of the allelic diversity in each region [with the exception of Australia (AUS)], reflects the high level of polymorphism at this locus, and this pattern suggests that HLA-B is extremely responsive to local variation in immune challenges. This is consistent with the highest proportion (96·7%), compared with the other loci, of statistical deviations from neutrality as assessed by Tajima’s tests51 of HLA-B, and also with other types of studies suggesting that this locus is under the strongest selection for heterozygous advantage.54,55 This extreme diversity may explain why, as the result of statistical limitations (e.g. mean sample size of only 127·1 ± 138·4 individuals in 90 populations analysed by Buhler and Sanchez-Mazas,51 compared with the large number of existing HLA-B alleles), the occurrence of rare HLA-B alleles is very heterogeneous among geographic regions and may give the impression that large numbers of regionally restricted alleles exist in all regions. South Amerindians however, carry some HLA-B alleles that are not detected (i.e.