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.