A high-titer amphotropic retroviral vector containing the neomycin resistance gene and a hybrid gamma-beta genomic human globin gene has been constructed. Mouse erythroleukemia cells infected with this virus were found to contain the full transcriptional unit of the transferred human globin gene by Southern blot analysis. These cells contain normally initiated, spliced, and terminated human glo...

We have investigated the DNase I hypersensitivity of a hybrid mouse/human beta-globin gene in erythroid and non-erythroid cells of transgenic mice, to examine the relationship between the chromatin structure and the expression of an exogenous gene. The hybrid globin gene was previously shown to be expressed specifically in erythroid cells in some transgenic lines. The maximal level of hybrid gl...

Somatic gene therapy of hemoglobinopathies depends initially on the demonstration of safe, efficient gene transfer and long-term, high-level expression of the transferred human beta-globin gene in animal models. We have used a beta-globin gene/beta-locus control region retroviral vector containing several modifications to optimize gene transfer and expression in a mouse transplant model. In thi...

Mammalian -globin loci contain multiple -like genes that are expressed at different times during development. The murine -globin locus contains two genes expressed during the embryo stage, Ey and h1, and two genes expressed at both the fetal and postnatal stages, -major and -minor. Studies of transgenic human -like globin loci in mice have suggested that expression of one gene at the locus will...

The alpha- and beta-globin gene families of jawed vertebrates have diversified with respect to both gene function and the developmental timing of gene expression. Phylogenetic reconstructions of globin gene family evolution have provided suggestive evidence that the developmental regulation of hemoglobin synthesis has evolved independently in multiple vertebrate lineages. For example, the embry...

The locus activation region (LAR) of the human beta-globin-like gene cluster is characterized by a group of four DNase I hypersensitive sites, which arise specifically in erythroid tissues and are required for a normal pattern of beta-globin-like gene expression. The hypersensitive sites are found at positions 6.1, 10.9, 14.7, and 18 kilobase pairs (kbp) 5' of the epsilon-globin gene. Recently ...

hemoglobin f (hbf, α 2 γ 2 ) is a major contributor to the clinical heterogeneity and ameliorating agent observed in patients with the β-globin disorders including β-thalassemia and sickle cell disease (scd). during fetal life, hbf is the major hemoglobin but is largely substituted by adult hemoglobin (hba, α 2 β 2 ) following a globin expression switch after birth. increased γ-globin expressio...

The determination of long segments of DNA sequences encompassing the beta- and alpha-globin gene clusters has provided an unprecedented data base for analysis of genome evolution and regulation of gene clusters. A newly developed computer tool kit generates local alignments between such long sequences in a space-efficient manner, helps the user analyze the alignments effectively, and finds cons...

Sickle cell disease is a hereditary, autosomal recessive pathology caused by the replacement of adenine thymin in position 6 beta globin gene, producing anomalous hemoglobin (hemoglobin S- HbS). It characterized chronic inflammatory state with hemolytic anemia and vaso-occlusive phenomena occurs when HbS gene homozygosis (SS) or heterozygosis, association other variant hemoglobins (SD, SC, SE) ...