Multiple origins of the human glycophorin Sta gene. Identification of hot spots for independent unequal homologous recombinations.

Human glycophorin Sta (HGpSta), one of the structural variants of erythrocyte membrane sialoglycoproteins, is encoded by a delta-alpha hybrid gene that arose from a single unequal crossover between the parent HGpB(delta) and HGpA(alpha) genes. We report here the identification of two new HGpSta genes (type A and type B) in four unrelated Sta heterozygotes from two ethnic groups. These Sta genes represent distinct genetic isoforms that differ from the previously reported Sta gene (type C) in the location of crossing-over sites. Comparison of nucleotide sequences among HGpB(delta), HGpA(alpha), and HGpSta type A genes revealed that the delta-alpha unequal crossover for the Sta type A gene occurred 110-246 base pairs downstream from pseudoexon III. In the crossing-over site of this Sta gene, an AT-rich sequence lying 3' to a nonameric palindrome was found to be highly similar to the lambda phage attachment site, att B, in inverted orientation. In the Sta type B gene, the delta-alpha crossing-over point was localized to an AG-rich sequence that is 302-490 base pairs downstream from pseudoexon III. Multiple lambda chi-like elements were identified at the crossover boundaries and within the breakpoint of this Sta gene. These results suggest strongly that recurrent and independent unequal recombination events have occurred in the formation of multiple Sta genes and that particular genomic sequences are important in defining the recombination sites for these homology-driven processes.