Researchers have identified gene variants present in some subpopulations of Africans that help these individuals ward off severe malaria. Their analysis suggests that these protective variants are a result of duplications, deletions and hybridization of two receptors associated with the membrane of red blood cells, which the malarial parasite Plasmodium falciparum uses to enter the cells. Malaria parasites cause human disease by invading and replicating inside red blood cells, a process that can lead to life-threatening complications that are a major cause of childhood mortality in Africa. Two receptors the parasite P. falciparum uses to enter the cells are GYPA and GYPB. Here, Ellen M. Leffler and colleagues identified gene variants that result in altered GYPA and GYPB receptors, and thus protect against malaria, in some Africans. They performed genome sequencing of 765 individuals from 10 ethnic groups in Gambia, Burkina Faso, Cameroon and Tanzania, also analyzing thousands of additional genomes from the 1000 Genomes Project and a database of severe cases of malaria. Among these individuals, the gene variant DUP4, in particular, was found to reduce the risk of severe malaria by an estimated 40%. Analysis of DUP4 suggests that this varied genetic element is a result of a loss of GYPB and a gain of two hybrid copies. Interestingly, DUP4 was only present in certain populations, particularly those of East African descent; for example, no copies were present among the 4,791 Gambian individuals in this study. The authors propose a number of reasons as to why DUP4 may not be more widespread, including the possibility that it emerged recently; alternatively, it may only protect against certain strains of P. falciparum that are specific to east Africa.