A distinct 5¢ flanking var gene region regulates Plasmodium falciparum variant erythrocyte surface antigen expression in placental malaria opposite sense when compared with the usual orientation of telomere-adjacent var genes. This unique arrangement might explain why the varCSA gene is relatively conserved in genetically distinct parasites despite being located in a highly recombinogenic chromosome compartment. The 5¢ untranslated region (UTR) of the varCSA-type sequence is also transcribed in placental isolates that bind to CSA, illustrating an important role for the unique 5¢ varCSA-type sequence in the regulation of var genes involved in malaria pathogenesis in pregnant women. However, this promoter is not always found to be transcribing var genes selected for expression of products that bind to CSA in vitro. Our work identifies a sequence tag for the identification of varCSA genes in placental isolates for the first time. IntroductionPlasmodium falciparum is responsible for nearly all malaria-specific mortality in endemic areas. Both morbidity and mortality associated with malaria have been attributed, in part, to the unique ability of P. falciparum-infected red blood cells (iRBCs) to adhere to small vascular endothelial cells and to uninfected erythrocytes (Wahlgren et al., 1999). Adhesion to host cells seems to be essential for parasite survival, as it prevents destruction of the iRBCs in the spleen. In holoendemic areas, novel parasite variants emerge in pregnant women that seem to be able to evade pre-existing immunity (Fried and Duffy, 1996). Falciparum malaria during the first pregnancy is a major cause of maternal anaemia and low birthweight (Steketee et al., 1996). Antibodies that develop after multiple pregnancies are associated with lower levels of iRBCs in the placenta, presumably by reducing sequestration (Fried et al., 1998). P. falciparum-infected erythrocytes adhere to syncytiothrophoblast cells in the placenta via chondroitin sulphate A (CSA). A direct correlation between CSA parasite sequestration and gestational malaria has been established. Cytoadherence of iRBCs is mediated by receptor-ligand interactions between parasite ligands on the infected erythrocyte membranes and cellular adhesion molecules on the surface of vascular endothelial cells such as CD36, ICAM-1, VCAM-1, Eselectin and CSA. Adhesion to different receptors is medi- ated by the parasite-derived antigen P. falciparum erythrocyte membrane protein 1 (PfEMP-1) encoded by ª 50 var genes per haploid genome (reviewed by Craig and Scherf, 2001). Most var genes are subtelomeric; however, clusters of var genes have also been found in internal chromosome positions. Members of the var gene family are subject to clonal antigenic variation, but only a single antigen variant is expressed on the iRBC surface in a mutually exclusive manner (Chen et al., 1998;Scherf et al., 1998). In situ activation of silent var genes appears to occur at the transcriptional level, as demonstrated by nuclear run-on assays in trophozoites (Scherf et al., 199...