A structural variant encoding hybrid glycophorins is associated with resistance to severe malaria

Human genetic variation in the region between FREM3 and GYPE was recently reported as associated with resistance to severe malaria in sub-Saharan Africa. By constructing a new imputation reference panel from sequence data with an increased representation of African populations, we show that the signal of association extends across the nearby genes GYPA and GYPB , which encode receptors for erythrocyte invasion by Plasmodium falciparum . Detailed analysis of large copy number variation reveals that the association can be explained by a complex structural variant that has lost GYPB but gained two hybrid genes, each with a GYPB extracellular domain and GYPA intracellular domain. This rearrangement, which is globally rare but carried by one in six children in parts of Kenya, encodes the Dantu blood group antigen, and reduces the risk of severe malaria by up to 40%. These findings provide the first direct evidence of the role malaria has played in shaping the landscape of variation at this polymorphic locus.