Interruption of the normal fetal-to-adult transition of hemoglobin expression 
should largely ameliorate sickle cell and beta-thalassemia syndromes. 
Achievement of this clinical goal requires a robust understanding of 
gamma-globin gene and protein silencing during human development. For this 
purpose, age-related changes in globin phenotypes of circulating human erythroid 
cells were examined from 5 umbilical cords, 99 infants, and 5 adult donors. 
Unexpectedly, an average of 95% of the cord blood erythrocytes and reticulocytes 
expressed HbA and the adult beta-globin gene, as well as HbF and the 
gamma-globin genes. The distribution of hemoglobin and globin gene expression 
then changed abruptly due to the expansion of cells lacking HbF or gamma-globin 
mRNA (silenced cells). In adult reticulocytes, less than 5% expressed 
gamma-globin mRNA. These data are consistent with a "switching" model in humans 
that initially results largely from gamma- and beta-globin gene coexpression and 
competition during fetal development. In contrast, early postnatal life is 
marked by the rapid accumulation of cells that possess undetectable gamma-globin 
mRNA and HbF. The silencing phenomenon is mediated by a mechanism of cellular 
replacement. This novel silencing pattern may be important for the development 
of HbF-enhancing therapies.