Expression of human globin genes in transgenic mice carrying the beta-globin gene cluster with a mutation causing G gamma beta + hereditary persistence of fetal hemoglobin.

We have introduced into the mouse germ line the 40-kilobase (kb) Kpn I fragment containing the beta-globin gene cluster from an individual with a non-deletion form of hereditary persistence of fetal hemoglobin (HPFH) believed to be due to a point mutation at position -202 of the G gamma-globin gene. The G gamma-globin gene, as well as the beta-globin gene, was expressed in adult erythroid tissues of the resulting transgenic mice. The level of expression of the G gamma-globin gene was about 20% of that of the beta-globin gene. Others have previously shown that cloned individual normal human beta- and gamma-globin genes containing a limited amount of 5'- and 3'-flanking DNA are expressed in a manner similar to that of their corresponding murine homologs during development in transgenic mice. In contrast, we have observed that the pattern of expression of the normal (non-mutated) A gamma- and beta-globin genes in the 40-kb insert was different from that of their corresponding murine homologs. The beta-globin gene remained inactive at the fetal stage, whereas the normal A gamma-globin gene was expressed beyond the embryonic (yolk sac) stage into the fetal stage of development and then became inactive in adult erythroid cells. The pattern of expression of the human globin transgenes during mouse development resembles that observed during human development. These results suggest that the gross organization of the human beta-like globin gene cluster is important for stage-specific expression of each human globin gene during development.