Geographic overlap between malaria and the occurrence of mutant hemoglobin and erythrocyte surface proteins has indicated that polymorphisms in human genes have been selected by severe malaria. Deletion of exon 3 in the glycophorin C gene (called GYPCDeltaex3 here) has been found in Melanesians; this alteration changes the serologic phenotype of the Gerbich (Ge) blood group system, resulting in Ge negativity. The GYPCDeltaex3 allele reaches a high frequency (46.5%) in coastal areas of Papua New Guinea where malaria is hyperendemic. The Plasmodium falciparum erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with high affinity to the surface of human erythrocytes. Here we show that the receptor for EBA140 is glycophorin C (GYPC) and that this interaction mediates a principal P. falciparum invasion pathway into human erythrocytes. EBA140 does not bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade such cells using this invasion pathway. This provides compelling evidence that Ge negativity has arisen in Melanesian populations through natural selection by severe malaria.

Erythrocyte polymorphisms, including ovalocytosis, have been associated with protection against malaria. This study in the Wosera, a malaria holoendemic region of Papua New Guinea, examined the genetic basis of ovalocytosis and its influence on susceptibility to malaria infection. Whereas previous studies showed significant associations between Southeast Asian ovalocytosis (caused by a 27-base pair deletion in the anion exchanger 1 protein gene) and protection from cerebral malaria, this mutation was observed in only 1 of 1019 individuals in the Wosera. Polymerase chain reaction strategies were developed to genotype individuals for the glycophorin C exon 3 deletion associated with Melanesian Gerbich negativity (GPC⌬ex3). This polymorphism was commonly observed in the study population (GPC⌬ex3 frequency ‫؍‬ 0.465, n ‫؍‬ 742). Although GPC⌬ex3 was significantly associated with increased ovalocytosis, it was not associated with differences in either Plasmodium falciparum or P vivax infection measured over the 7-month study period. Future case-control studies will determine if GPC⌬ex3 reduces susceptibility to malaria morbidity. IntroductionThe geographic overlap between malaria and red blood cell (RBC) disorders led Haldane to hypothesize that many polymorphisms in the human genome have arisen by natural selection to protect from severe malaria infection and thereby increase reproductive fitness of populations living in malaria endemic regions. 1 In Papua New Guinea, Southeast Asian ovalocytosis, caused by a 27-base pair (bp) deletion in the anion exchanger 1 protein gene (AE1⌬27), is observed in many coastal malaria holoendemic areas and is associated with protection from cerebral malaria. 2,3 While AE1⌬27 has not been reported in residents of the malaria holoendemic Wosera region of Papua New Guinea, 2 ovalocytic RBCs are common.Additional polymorphisms characterizing the human population in the Wosera include an exon 3 deletion of the integral membrane sialoglycoprotein glycophorin C (GPC). [4][5][6] This deletion (GPC⌬ex3) changes serologic phenotypes of the Gerbich (Ge) blood group system in Melanesians. 7 Because GPC is involved in maintaining the integral RBC membrane lattice, the association between GPC⌬ex3 and ovalocytosis was tested. Furthermore, because GPC⌬ex3 is distributed within a malaria holoendemic region, we tested the association between GPC⌬ex3 and susceptibility to malaria infection. Study design Study population and malariaThe study was conducted in the Wosera region of Papua New Guinea, where all 4 human Plasmodium species are transmitted year-round. 8 Blood samples were collected monthly from permanent residents (median age, 17 years; range, 1-86 years) of 6 villages within the Wosera from July 1998 to January 1999. The human investigations institutional review boards of Case Western Reserve University, University Hospitals of Cleveland, and the Papua New Guinea Medical Research Advisory Committee approved all protocols. Malaria and red blood cell morphologyThick and thin films stained with...