MOLECULAR-GENETICS OF THE GLYCOPHORIN GENE FAMILY, THE ANTIGENS FOR MNSS BLOOD-GROUPS - MULTIPLE GENE REARRANGEMENTS AND MODULATIONS OF SPLICE-SITE USAGE RESULT IN EXTENSIVE DIVERSIFICATION

The purpose of the review is to describe a system of human erythrocyte membrane glycoproteins exhibiting extensive diversity, Glycophorins A and B (GPA and GPB) are the antigens of the MNSs blood groups; thus i ndividuals bearing variant glycophorins can be readily identified by s erological typing. Examination of the wide array of variants of these antigens showed that they include many forms, possibly made evident by lack of constraints due to the apparent dispensability of the parent molecules. This article reviews the molecular genetics of 25 variants of the glycophorin gene family, whose common denominator is that they arise from unequal gene recombinations or gene conversions coupled to splice site mutations. Most rearrangements occurred within a 2-kb regi on mainly within GPA and GPB of the gene family and only rarely within the third member, GPE. The key feature is the shuffling of sequences within two specific exons (one of which is silent), homologous in the two parent genes. This has resulted in expression of a mosaic of seque nces within this region, leading to polymorphism. The common pattern o f recombinations coupled to pre-mRNA splicing was the predominant mech anism of the origin of glycophorin diversity, Thus far this mechanism appears to be unique among human gene families. It could have occurred by chance rearrangements among closely linked genes and been driven b y a biological advantage, not as yet identified. This remains to be es tablished. Nevertheless, gene rearrangements observed here are akin to those reported for the major histocompatibility complex (MHC). In the glycophorin family the small size of the region within which gene int eractions have occurred and the participation of essentially only two alleles makes this relatively simpler system more focused and easier t o dissect and describe molecularly. (C) 1995 Wiley-Liss, Inc.