The organization of alpha-globin genes in normal white European, normal Algerian, and alpha-thalassemic Algerian DNA was examined by restriction endonuclease mapping using HindIII, HpaI, Bamhi, EcoRI, BgIII, and PstI. The results for normal DNA confirm and add to the findings of Surrey et al. and Orkin; the two alpha-genes are approximately 3.0 kb apart. The restriction enzymes BgIII and HpaL cut between the two alpha-genes. Four PstL sites are located: two surrounding each alpha-gene. The physical maps for a number of Algerian controls (normal alpha- and beta-globin biosynthesis profiles) are identical to that of the European controls. The Algerian alpha- thalassemic presenting with HbH disease was found to be homozygous for a 3.5–3.7 kb deletion at the alpha-gene locus, leaving one alpha-gene per chromosome. The patient's mother and father are both found to be heterozygous for this deletion. An unaffected sibling carries both normal chromosomes. The deletion could be the result of a Lepore-like crossover fusion event between the two alpha-globin genes, or of a 3.7 kb deletion of either the entire 5′ alpha-gene or the entire 3′ alpha- gene. The Algerian case of HbH disease studied differs from Asian cases in both the mode of inheritance and the molecular pathology of the alpha-thalassemia mutation. If this type of deletion is the major cause of Algerian alpha-thalassemia, it would explain the apparent absence of Hydrops fetalis in this geographical area.

Many human globin-chain mutants contain amino acid replacements that result from single base changes in the corresponding globin gene. Using recombinants, the coding sequences of each of the alpha-, beta-, Ggamma- , and Agamma-globin genes have now been determined. Those sequences of DNA that are cleaved by a number of specific restriction endonucleases have been identified and accurately positioned. Mutations at these sequences abolish the restriction site, and therefore, the pattern of DNA fragments containing hybridizing globin-gene sequences is altered compared to DNA from normal persons. This allows the identification of one of a pair of cross-hybridizing human globin-gene sequences, as is shown here for the two alpha-globin, the two gamma-globin, and the delta- and beta-globin genes.