The authors constructed a "minilocus" containing the 5' and 3' flanking regions of the human β-globin locus and the β-globin gene. This minilocus was expressed tissue-specifically in transgenic mice at a level directly related to its copy number, independent of its position in the genome. The expression per gene copy was consistent across all mice and comparable to that of the endogenous mouse β-globin gene. This indicates that the DNA regions flanking the human β-globin locus contain dominant regulatory sequences that specify position-independent expression and activate the complete human multigene β-globin locus. The study also mapped DNase I-hypersensitive sites 5' and 3' of the β-globin gene, which are erythroid-cell-specific and present during any erythroid developmental stage. These hypersensitive sites are crucial for the position-independent expression of the β-globin gene. The authors propose a model for the mechanism of globin switching during development, suggesting that the dominant control region determines the activity of the locus, while the hypersensitive sites render the chromatin accessible to trans-acting factors. This work has implications for gene therapy, as it suggests that the inclusion of these dominant control regions in retroviral vectors or transfection systems could allow for completely regulated expression of genes like the β-globin gene.The authors constructed a "minilocus" containing the 5' and 3' flanking regions of the human β-globin locus and the β-globin gene. This minilocus was expressed tissue-specifically in transgenic mice at a level directly related to its copy number, independent of its position in the genome. The expression per gene copy was consistent across all mice and comparable to that of the endogenous mouse β-globin gene. This indicates that the DNA regions flanking the human β-globin locus contain dominant regulatory sequences that specify position-independent expression and activate the complete human multigene β-globin locus. The study also mapped DNase I-hypersensitive sites 5' and 3' of the β-globin gene, which are erythroid-cell-specific and present during any erythroid developmental stage. These hypersensitive sites are crucial for the position-independent expression of the β-globin gene. The authors propose a model for the mechanism of globin switching during development, suggesting that the dominant control region determines the activity of the locus, while the hypersensitive sites render the chromatin accessible to trans-acting factors. This work has implications for gene therapy, as it suggests that the inclusion of these dominant control regions in retroviral vectors or transfection systems could allow for completely regulated expression of genes like the β-globin gene.