The RhD protein which is the RHD gene product and a major component of the Rh blood group system carries the strongest blood group immunogen, the D-antigen. This antigen is absent in a significant minority of the human population (RhD-negatives) due to RHD deletion or alternation. The origin and persistence of this RhD polymorphism is an old evolutionary enigma. Before the advent of modern medicine, the carriers of the rarer allele (e.g. RhD-negative women in the population of RhD-positives or RhD-positive men in the population of RhD-negatives) were at a disadvantage as some of their children (RhD-positive children born to pre-immunized RhD-negative mothers) were at a higher risk of foetal or newborn death or health impairment from haemolytic disease. Therefore, the RhD-polymorphism should be unstable, unless the disadvantage of carriers of the locally less abundant allele is counterbalanced by, for example, higher viability of the heterozygotes. Here we demonstrated for the first time that among Toxoplasma-free subjects the RhD-negative men had faster reaction times than Rh-positive subjects and showed that heterozygous men with both the RhD plus and RhD minus alleles were protected against prolongation of reaction times caused by infection with the common protozoan parasite Toxoplasma gondii. Our results suggest that the balancing selection favouring heterozygotes could explain the origin and stability of the RhD polymorphism. Moreover, an unequal prevalence of toxoplasmosis in different countries could explain pronounced differences in frequencies of RhD-negative phenotype in geographically distinct populations.

The erythrocyte chemokine receptor, a receptor for Plasmodium vivax, carries the antigens of the Duffy blood group system. Sequence analysis of reticulocyte RNA from individuals of known Duffy phenotype showed that the Fya antigen differs from the Fyb antigen as a result of a single nucleotide difference (A131 or G) encoding amino acid Gly44 (Fya) or Asp (Fyb) in the N-terminal extracellular domain of the glycoprotein. Evidence is presented for two different genetic backgrounds giving rise to the Fy(a-b-) phenotype. The most likely genetic mechanism in most individuals of the Fy(a-b-) phenotype is down-regulation of Duffy glycoprotein mRNA. However, the Duffy gene from a very rare Caucasian individual (AZ) with the Fy(a-b-) phenotype has a 14 base-pair deletion (nucleotides 287-301) resulting in a frameshift which introduces a stop codon and produces a putative truncated 118 amino acid protein. The occurrence of this mutation in an apparently healthy individual raises questions about the functional importance of the Duffy glycoprotein not only in normal erythrocytes but also in all human cells and tissues.

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