A comprehensive understanding of the evolutionary history of Gamma-globin genes and the mammalian Beta-globin gene clusters in which they occur is being sought. A principal goal is to uncover new clues about the ontogenetic program which controls human fetal hemoglobin synthesis. The Gamma-globin genes of humans and other simian primates encode the polypeptide which distinguishes fetal hemoglobin (Alpha 2 Gamma 2) from embryonic (Zeta 2 Epsilon 2; Alpha 2 Epsilon 2) and adult (Alpha 2 Delta 2; Alpha 2 Beta 2) hemoglobins. As rabbits and mice have Gamma genes expressed along with Epsilon genes only during embryonic life, the first primates possibly had embryonic Gamma genes rather than fetal ones. If so, recruitment of Gamma to be a fetal gene occurred in later primates ancestral to the simian primates (i.e. to Anthropoidea). Phylogenetic tests of this hypothesis will provide new data on conserved functionally active DNA sequences within the human Beta-globin gene cluster and on organizational features of the human cluster that may be implicated in the developmental switches from Epsilon to Gamma and then to Delta and Beta gene expression. Detailed characterizations of the Delta-globin gene clusters of lower (prosimian) and higher (simian) primates and extensive DNA sequencing on Gamma and other gene regions, especially between Gamma and Delta loci, will be carried out. This primate inter Gamma - Delta region contains the non-expressed Psi Beta1 locus which shares with the expressed goat embryonic Epsilon II locus a common ancestral gene called Eta to distinguish it from Epsilon, Gamma, Delta and Beta loci. Extending the DNA analyses to such non-primate mammals as opossum, armadillo, tree shrew, and flying lemur will furnish an enlarged data base with which to improve a proposed five loci model 5' - Epsilon - Gamma - Eta - Delta - Beta-3' for the Beta-globin gene clusters of early mammals and proto-primates by allowing more accurate deductions to made on the lengths of intergenic regions and the nature of their sequences. In addition parallel studies of the hhemoglobin chains produced by fetuses of two lower primates, galago and tarsier, will provide pertinent data for testing the embryonic Gamma (proto-primate) to fetal Gamma (proto-Anthropoidea) recruitment hypothesis. The extensive sequence data to be gathered on simian primates should then help reveal evolutionary changes which occurred in overall organization of the proto-Anthropoidea Beta-globin gene cluster and in positioning of specific sequences within the cluster. This data will also characterize the finer organization and recent sequence patterns which evolved in the human Beta--globin gene cluster.
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