Boundaries of gene conversion within the duplicated human alpha-globin genes. Concerted evolution by segmental recombination.

The human adult alpha-globin genes, alpha 1 and alpha 2, are embedded in homologous duplication units, each of which spans approximately 4 kilobase pairs of chromosomal DNA. Previous studies established that the 3'-ends of the duplication units are located adjacent to the polyadenylation sites of the two genes. We have now determined the 5'-boundary of the homology which includes both the structural genes and their upstream sequences. The 5'-flanking regions of alpha 1 and alpha 2 are perfectly homologous for 868 base pairs, with the exception of two single nucleotide differences. This is in contrast to the considerable divergence of the 3'-ends of these loci. Since the alpha-genes undergo concerted evolution by homologous unequal crossing over and/or gene conversion, the presence of adjacent regions with different degrees of homology indicates that this process is segmental. Furthermore, we have determined that an alpha-thal-2 gene, a variant alpha-globin allele resulting from unequal crossing over between normal alpha 1 and alpha 2 genes, has a mosaic arrangement of parental sequences. This patchwork structure may have arisen from a single recombination event which was limited in both the 5' and 3' directions by flanking non-homologies and in which mismatch repair occurred in a heteroduplex intermediate. Unequal crossing over and gene conversion of this type may effect the segmental concerted evolution of the human alpha-globin locus. Restriction mapping of additional alpha-thal-2 genes and of the reciprocal triplicated alpha-gene complex was consistent with this hypothesis.