Clinical background: Sickle cell anemia and beta thalassemia result from mutation and absence, respectively, of beta globin chain polypeptides. The human beta globin gene cluster spans about 45 kb on chromosome 11 and includes 5 functional genes and 1 pseudogene. The chromosomal order of the genes is: 5'- epsilon, gamma G, gamma A, beta 1 pseudogene, delta, beta -3'. These beta-like genes have the same overall exonic structure and are thought to be derived from one ancestral gene. The epsilon and the two gamma globin genes are expressed in early embryonic and fetal erythroid tissues, while delta and beta globin genes are expressed in adult life. Two epsilon chains combine with two zeta chains to constitute the embryonic hemoglobin Hb Gower I; two epsilon chains together with two alpha chains form the embryonic Hb Gower II. Two gamma chains combine with two alpha chains to make fetal hemoglobin HbF. Finally, two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin. More information
The human alpha globin gene cluster is located on chromosome 16 and spans about 30 kb. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, while they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin. Alpha chains combined with delta chains constitute HbA2, which together with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some non-deletion alpha thalassemias have also been reported. HS-40 is the major regulatory element of the human alpha-globin locus and is located 40 kb upstream the zeta-globin gene. Deletion of only the HS40 region has also been described.