One explanation for the remarkable diversity of the MHC — which is the most polymorphic gene cluster in the human genome — is that genetic diversity is the result of pathogen-driven selection processes. Although there is some evidence indicating that this is the case, until now, there has been little direct evidence to support this idea.

If diversity is the result of pathogen-driven selection, then one prediction would be that, in geographical regions of high pathogen diversity, humans should have increased diversity of HLA genes in relation to their average genomic diversity. To test this, the authors used 3 types of information: data on the genetic diversity of HLA class I molecules from 61 human populations; estimates of pathogen richness (that is, the total number of intracellular pathogens that are known to be present in each country); and the geographical distance of each population from East Africa (to control for the effect of past colonization history).

The authors found that human populations located further from East Africa had lower genetic variability and that human colonization history accounted for 17–39% of the diversity of HLA genes. The remaining diversity was significantly correlated with pathogen richness: that is, a population exposed to a more diverse range of pathogens has greater HLA diversity than one exposed to fewer pathogens. The results showed that pathogens (mainly viruses) exerted the greatest pressure on genes in the HLA-B locus; interestingly, it has recently been shown that HLA-B genes could have a larger role in containing viral infections than HLA-A genes.

These results show that human colonization history has been important in shaping the diversity of the HLA locus, but pathogen-driven selection has also had a role.