An evolutionary perspective of how infection drives human genome diversity: the case of malaria

• The red blood cell harbours many parallel genetic adaptations to malaria.
• ATP2B4, encoding for erythrocytes major Ca2+ transporter, is a recently identified novel resistance locus.
• Selective and biological interactions exist among malaria protective variants.
• Many susceptibility alleles remain to be uncovered and may affect the homeostasis of the immune system.
• Genetic factors protecting from malaria could also be advantageous for parasite transmission.

Infection with malaria parasites has imposed a strong selective pressure on the human genome, promoting the convergent evolution of a diverse range of genetic adaptations, many of which are harboured by the red blood cell, which hosts the pathogenic stage of the Plasmodium life cycle. Recent genome-wide and multi-centre association studies of severe malaria have consistently identified ATP2B4, encoding the major Ca2+ pump of erythrocytes, as a novel resistance locus. Evidence is also accumulating that interaction occurs among resistance loci, the most recent example being negative epistasis among alpha-thalassemia and haptoglobin type 2. Finally, studies on the effect of haemoglobin S and C on parasite transmission to mosquitoes have suggested that protective variants could increase in frequency enhancing parasite fitness.