The promoter and exon 1 sequences of the genes encoding erythrocyte glycophorins GPA, GPB and GPE were investigated in detail, both from a genomic clone sorted out of a human leukocyte library and from genomic clones obtained by polymerase chain reaction amplification of total genomic DNA from control individuals and from GAP and/or GPB deletion variants. The three exons 1 and upstream sequences were shown to be highly homologous with only a few point mutations that did not affect the potential cis-acting elements (CACCC, NF-E1 and NF-E2) that are present in the same position within the three genes. Moreover, these genes share the same transcription start point. Analysis of the exon 1 and promoter sequences together with the gene defects occurring in the GP variants indicate that unequal cross-overs between the three genes are responsible for deletions and the generation of hybrid gene structures in which the promoter of one gene is brought close to another gene of the family. On the basis of these studies, a model of the gene organization is proposed to explain the rearrangements occurring in the variants.