Mice with radiation-induced, alpha-chain deficiencies or a beta-chain gene duplication will be used to determine the genetic and molecular bases for deviations from expected ratios in the concentrations of parental-type beta-chain polypeptides in hemoglobin of alpha-thalassemic mice. The data obtained through amino acid analyses and isotopic labeling techniques will contribute to the basic knowledge on the ontogeny of hemoglobin development in animals which express altered concentrations of alpha and beta chains as adults. Whether or not similar alterations are also expressed among the embryonic hemoglobins of these genetically abnormal mice will also be studied. Genetic, physiologic and pharmacologic methods will be used in attempts to alter the synthesis of non-alpha-chain polypeptides in mice with alpha thalassemia. Additional progeny of irradiated mice will be screened in search for other alpha and beta chain structural or regulatory mutants that would be of value for basic studies on hemoglobin synthesis; e.g., mouse models of sickle-cell disease or beta thalassemia. Congenic strains will be produced of alpha-thalassemic mice and of any beta-thalassemic or hemoglobin structural mutants induced during this study. The congenic mice will be used in experiments that attempt to "genetically-rectify" the hematologic abnormality via in vivo transfer of normal, functional genes into defective hematopoietic stem cells and subsequent transfer of these treated cells back into the defective animal. If the treated cells function well and progressively repopulate the host's hematopoietic system, tests will be made of the ability to transfer extra embryonic or fetal hemoglobin genes into stem cells as a possible means of producing artifically functional stem cells with persistence of fetal hemoglobin to ameliorate symptoms of sickle-cell anemia.