Diversity of HLA genotypes in humans is shaped to a significant degree by pathogens

The great physical diversity that evolution has forged in human beings is in evidence wherever we look, but the genes exhibiting the greatest diversity at the DNA level happen to function in a wholly invisible process: immunity. Genes encoding the Human Leukocyte Antigen (HLA) proteins are among the most diverse in the human genome, and scientists have proposed a number of hypotheses to explain why.

This week, researchers report new findings that support the idea that the striking diversity of HLA genotypes in humans is shaped to a significant degree by the different sets of pathogenic species encountered by different human populations around the world.

The findings are reported in the June 7 issue of Current Biology by Dr. Franck Prugnolle and colleagues at the University of Cambridge.

HLA class I proteins are critical players in the recognition of antigens--bits of foreign protein derived from invading pathogens--and in the presentation of the antigens on the surfaces of cells. HLA proteins and the antigens they present are recognized by specialized immune cells, resulting in immune responses that combat disease. But why should HLA genes be so diverse? Numerous factors could contribute, but a leading idea has been that pathogens themselves play a role. Past work had offered clues to this effect--for example, individuals with some HLA genotypes are more susceptible (or more resistant) to some pathogens than others. If different versions of HLA proteins can influence how the immune system deals with a particular pathogen, it follows that, in theory, HLA genes should evolve to deal most effectively with the various antigens humans encounter.

This kind of evolution, leading to diverse HLA genotypes in which individuals possess two different versions, or alleles, of the various HLA genes, forms the basis for the idea of "pathogen-driven balancing selection," or PDBS.

In their new work, the researchers set out to test the PDBS hypothesis by analyzing HLA sequences from 61 native human populations worldwide and comparing the degree of HLA diversity to the number of different pathogens known to be present in each population's geographic region.

Because other factors, such as a population's migratory history, could influence genetic diversity in a general way, the authors also compared HLA diversity with the general genetic diversity expected for the population's location (this research group previously showed close correlation between diversity and location along ancient colonization routes).

The authors found that although human colonization history accounted for a certain degree of HLA diversity (as it does for other genes as well), the "local" richness of pathogen diversity also correlated significantly with the HLA diversity exhibited by individual populations, supporting the PDBS hypothesis. High HLA diversity tended to correlate with high pathogen diversity. In addition, the authors found that this correlation was especially strong for a particular type of HLA gene, HLA B. This finding is in agreement with past immunological and genetic studies showing that not all HLA class I proteins play identical roles and suggesting that pathogens--notably, viruses--may exert stronger evolutionary pressure on HLA B than on other HLA genes.