The solution to the fetus's problem of getting oxygen from its mother's blood involves the development of a fetal hemoglobin. The hemoglobin in fetal red blood cells differs slightly from that in adult corpuscles. Two of the four peptides of the fetal and adult hemoglobin chains are identical - the alpha chains - but adult hemoglobin has two beta chains, while the fetus has two gamma chains. Normal beta-chains bind the natural regulator diphosphoglycerate, which assists in the unloading of oxygen. The gamma-chain isoforms do not bind diphosphoglycerate as well and therefore have a higher affinity for oxygen. In the low-oxygen environment of the placenta, oxygen is released from adult hemoglobin. In this same environment, fetal hemoglobin does not give away oxygen, but binds it. This small difference in oxygen affinity mediates the transfer of oxygen from the mother to the fetus. Within the fetus, the myoglobin of the fetal muscles has an even higher affinity for oxygen, so oxygen molecules pass from fetal hemoglobin for storage and use in the fetal muscles. Fetal hemoglobin is not deleterious to the newborn, and in humans, the replacement of fetal hemoglobin-containing blood cells with adult hemoglobin-containing blood cells is not complete until about 6 months after birth.

The gamma locus determines the gamma chain of fetal hemoglobin (alpha-2/gamma-2). Two types of gamma polypeptide chains do exist. Although not distinguishable by most of the physical methods used, sequencing has shown at least 1 amino acid difference: at position 136 one type has glycine (G-gamma) and the second type has alanine (A-gamma). The ratio of G-gamma to A-gamma is fairly constant (about 7:3) during the fetal period. The ratio declines progressively during the postnatal gamma-to-beta switch, leading to an average value of 2:3 in the small residual amount of Hb F detectable in normal adult blood. In a normal human genome there are usually four gamma structural loci, two on each autosome that presumably arose by gene duplication.

A number of mutations have been identified that interfere with the normal process of hemoglobin switching and result in hereditary persistence of fetal hemoglobin. Several single-base substitutions located within the promoter regions of the gamma genes appear to be responsible for the hereditary persistence of fetal hemoglobin phenotype.

Hematologic correlations with restriction mapping suggest that a region of DNA near the 5-prime end of the delta gene may be involved in the cis-suppression of gamma-globin gene expression in adults. The beta-globin locus control region is a powerful regulatory element required for high-level globin gene expression. Nucleotide sequences of the beta-globin locus control region were originally described as a cluster of DNase I hypersensitive sites 6 to 18 kb upstream to the epsilon-globin gene. The hemoglobin beta locus control region is thought to organize the entire 60-kb beta-globin gene cluster into an active chromatin domain and allows a high level of position-independent, copy number-dependent, and erythroid-specific globin gene expression.