Blood group polymorphisms: molecular approach and biological significance

Genes for 20 of the 23 human blood group systems have now been cloned and the molecular bases of the important polymorphisms within most of these systems are known. Most blood group polymorphisms are due to missense mutations resulting in amino acid substitutions, but other types of mutation are involved in blood group polymorphism including gene deletion, single base deletion, and exchange of genetic material between homologous genes. All the polymorphisms of the Kell system, for example, result from missense mutations. Comparison of the position of these mutations within the KEL gene with clusters of antigens determined by an immunochemical technique, suggests that the Kell-system antigens are not linear and are probably discontinuous. The biological significance of the proteins and glycoproteins carrying many of the blood group antigens is known, or at least can be speculated upon. Identification of the nonsense mutations responsible for some null-phenotypes has shown that these macromolecules are not usually essential for a healthy life. Little is known, however, about the biological significance of the blood group polymorphisms. Many macromolecules carrying blood group activity are receptors for pathogenic micro-organisms and these pathogens may well have played an important part in the evolution of blood group polymorphism. The Duffy-glycoprotein is a chemokine receptor, but also a receptor for the malarial parasite Plasmodium vivax A mutation within an erythroid-specific transcription factor binding site within the FY gene, common in people of African origin but rare in other ethnic groups, results in the absence of the glycoprotein from red cells and, therefore, resistance to P. vivax infection, but presence of the glycoprotein in other tissues, reducing any potential selective disadvantage.