The objectives of this proposal are to carry out three related studies on the molecular genetics of chromosome 21. 1. Characterization of DNA sequences which are involved in chromosomal breakage and ring formation. We have identified a 2.1 kb EcoRI fragment (named 231C) which maps at the breakpoints of a ring 21 chromosome [r21(p13q22.3)]. Upon DNA cloning and sequencing of this region, in both the normal 21 and the r21 chromosome, we will identify sequences associated with this chromosomal breakage and reunion, and we will better understand the pathophysiologic mechanism of ring formation. 2. Construction of a linkage map of DNA sequences located on chromosome 21. This linkage map will include several single copy DNA fragments, the superoxide dismutase gene (SOD-1) and the homocystinuria phenotype due to cystathionine Beta synthase (CBetaS) deficiency. 3. Test of the hypothesis that certain chromosome 21s have an increased tendency to undergo non-disjunction (NDJ) and, therefore, produce Down Syndrome (DS). Using haplotype analysis of four different very closely linked DNA polymorphic sites which map to the proximal long arm of chromosome 21 we have demonstrated in a pilot study in the Greek population that one particular chromosome 21 is commonly associated with NDJ. Further study of this phenomenon will be carried out in at least one more ethnic group not genetically associated with Greeks. DNA polymorphic markers adjacent to single copy chromosome 21-specific centromeric sequences will be used to further characterize the target chromosome 21. Molecular cloning of the DNA of the different types of chromosome 21 with different risk for NDJ may reveal important information about the genomic organization of DNA in """"""""sticky"""""""" chromosomes.
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