The goal of this study is to define the structure of genes in inherited hematologic disorders in the Beta thalassemias and sickle cell anemia. During the past two years, I have defined new polymorphisms in DNA associated with the Beta thalassemia syndromes and have contributed new information related to the underlying defect in certain forms of Beta thalassemia as well. During this time, I have also investigated gene organization of hemoglobin Miyada DNA, a rare hemoglobin mutant. Now I will use my experience to develop new techniques which should permit a more detailed analysis of the structure of normal and abnormal globin genes. New procedures will be developed to detect smaller fragments of DNA and their organization than currently available methods permit. Additionally, new radioactive probes will be used to detect changes in globin gene structure and organzation in cellular DNA. These new procedures will be applied to analyses of DNA from patients with Beta thalassemia and sickle cell anemia using probes from the Gamma, Beta and Alpha loci. Several types of changes will be sought. These include: (1) Changes in structure within the Beta globin genes in the thalassemias which may explain the underlying defect in these disorders; (2) Changes in Alpha, Delta and Gamma genes associated with the Beta thalassemia and sickle genotypes which may reflect a modulation of thee abnormal genes in certain subgroups of patients with these disorders; and (3) A search for polymorphisms linked to these genes which may be useful in determining the origin of these genes in evolution and potentially for antenatal diagnosis.