These deletions involve one entire alpha-globin gene (either alpha2 or alpha1), part of the alpha2-globin gene, or the 5' end of alpha2 and the 3' end of alpha1, resulting in a functional alpha2alpha1 hybrid gene. The total number of deletions discovered thus far are eight (Fig. 21); each of these is listed separately on pages 265 through 270.
In the psialpha1, alpha2, and alpha1 regions we find X, Y, and Z homology boxes. The abnormality caused by mispairing of these homologous sequences, followed by unequal crossover results in a deletion (-alpha) and a triple alpha (alphaalphaalpha) (see Fig. 22). These events can be further divided, depending on the exact location of the crossover in Z sequences. The so-called -alpha(3.7-I), -alpha(3.7-II), and -alpha(3.7-III) deletions can be differentiated by Southern blot hybridization and by PCR methodology using specific primers.
Four of the eight deletions are rare abnormalities and are observed in only one or a few families [the (alpha)alpha(5.3); -alpha(2.7); -alpha(3.5); -alpha(18+) deletions]. This is not the case for the different -alpha(3.7) and -alpha(4.2) deletions which occur worldwide and often at high frequencies. The most common alpha-thal-2 is the -alpha(3.7-I) type; high frequencies are observed in African populations, India, Nepal, Sardinia, and many other Mediterranean populations, China, and other East Asian countries. The -alpha(3.7-II) type is found mainly in India and Nepal, and the -alpha(3.7-III) type in Micronesia and Polynesia. Finally, the -alpha(4.2) deletion is present in Indian populations, Melanesia, Thailand, and some other Southeast Asian countries. The high frequencies of these deletions are related to the (past) occurrence of malaria and are often higher than 20% in malarious regions and in some (like Indian and Papuan peoples) even over 70%. These types of alpha-thal are, together, probably the most common single gene disorder in the world.
FIG. 21. The eight deletions resulting in chromosomes carrying one intact alpha-globin gene (modified after Higgs, 1993).
FIG. 22. Single gene deletions in the alpha-globin gene cluster. A. The X, Y, and Z homology boxes in the region of the alpha-globin genes. B. Mispairing and crossover in the Z homology box produces a -alpha(3.7) chromosome containing a 3.7 kb deletion. The reciprocal of this event is a triple alpha chromosome. C. Mispairing and crossover in the X homology box produces a single alpha chromosome with a 4.2 kb deletion (from Kazazian, 1990).