Human RBCs glycophorins are integral membrane proteins rich in sialic acids that carry blood group antigenic determinants and serve as ligands for viruses, bacteria, and parasites. These molecules have long been used as a general model of membrane proteins and as markers to study normal and pathological differentiation of the erythroid tissue. The RBC glycophorins known as GPA, GPB, GPC, GPD, and GPE have recently been fully characterized at both the protein and the DNA levels, and these studies have demonstrated conclusively that these molecules can be subdivided into two groups that are distinguished by distinct properties. The first group includes the major proteins GPA and GPB, which carry the MN and Ss blood group antigens, respectively, and a recently characterized protein, GPE, presumably expressed at a low level on RBCs. All three proteins are structurally homologous and are essentially erythroid specific. The respective genes are also strikingly homologous up to a transition site defined by an Alu repeat sequence located about 1 Kb downstream from the exon encoding the transmembrane regions. Downstream of the transition site, the GPB and GPE sequences are still homologous, but diverge completely from those of GPA. The three glycophorin genes are organized in tandem on chromosome 4q28-q31, and define a small gene cluster that presumably evolved by duplication from a common ancestral gene. Most likely two sequential duplications occurred, the first, about 9 to 35 million years ago, generated a direct precursor of the GPA gene, and the second, about 5 to 21 million years ago, generated the GPB and GPE genes and that involved a gene that acquired its specific 3' end by homologous recombination through Alu repeats. Numerous variants of GPA and GPB usually detected by abnormal expression of the blood group MNSs antigens are known. An increasing number of these variants have been structurally defined by protein and molecular genetic analyses, and have been shown to result from point mutations, gene deletions, hybrid gene fusion products generated by unequal crossing-over (not at Alu repeats), and microconversion events. The second group of RBC membrane glycophorins includes the minor proteins GPC and GPD both of which carry blood group Gerbich antigens. Protein and nucleic acid analysis indicated that GPD is a truncated form of GPC in its N-terminal region, and that both proteins are produced by a unique gene called GE (Gerbich), which is present as a single copy per haploid genome and is located on chromosome 2q14-q21.(ABSTRACT TRUNCATED AT 400 WORDS)