Fetal hemoglobin (HbF), the predominant hemoglobin in the fetus, is a mixture of 
two molecular species (alpha(2)(G)gamma(2) and alpha(2)(A)gamma(2)) that differ 
only at position 136 reflecting the products of two nonallelic gamma-globin 
genes. At the time of birth, HbF accounts for approximately 70% of the total Hb. 
The (G)gamma:(A)gamma globin ratio in the HbF of normal newborn is 70:30 whereas 
in the trace amounts of HbF that is found in the adult it reverses to 40:60 
because of a gamma- to beta-globin gene switch. Alterations of these ratios are 
indicative of a molecular defect at the level of the HbF synthesis. Qualitative 
hemoglobinopathies due to (G)gamma and (A)gamma chain structural variants, and 
quantitative hemoglobinopathies affecting the synthesis of HbF such as 
gamma-thalassemias, duplications, triplications, and even sextuplications of the 
gamma-globin genes, which may be detected in newborn blood lysates, have been 
described. Moreover, several pathological and nonpathological conditions 
affecting the beta-globin gene cluster, such as beta-thalassemia, sickle cell 
disease, deltabeta-thalassemia, and hereditary persistence of HbF syndromes, are 
characterized by the continued synthesis of gamma-globin chains in the adult 
life. Studies of these natural mutants associated with increased synthesis of 
HbF in adult life have provided considerable insight into the understanding of 
the control of globin gene expression and Hb switching.