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.

Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Antonarakis, S E; Petersen, M B; McInnis, M G et al. (1992) The meiotic stage of nondisjunction in trisomy 21: determination by using DNA polymorphisms. Am J Hum Genet 50:544-50
Antonarakis, S E (1991) Parental origin of the extra chromosome in trisomy 21 as indicated by analysis of DNA polymorphisms. Down Syndrome Collaborative Group. N Engl J Med 324:872-6
Ladias, J A; Kwiterovich Jr, P O; Smith, H H et al. (1990) Apolipoprotein A1 Baltimore (Arg10----Leu), a new ApoA1 variant. Hum Genet 84:439-45
Petersen, M B; Economou, E P; Slaugenhaupt, S A et al. (1990) Linkage analysis of the human HMG14 gene on chromosome 21 using a GT dinucleotide repeat as polymorphic marker. Genomics 7:136-8
Stetten, G; Tuck-Muller, C M; Blakemore, K J et al. (1990) Evidence for involvement of a Robertsonian translocation 13 chromosome in formation of a ring chromosome 13. Mol Biol Med 7:479-84
Ladias, J A; Kwiterovich Jr, P O; Smith, H H et al. (1989) Apolipoprotein B-100 Hopkins (arginine4019----tryptophan). A new apolipoprotein B-100 variant in a family with premature atherosclerosis and hyperapobetalipoproteinemia. JAMA 262:1980-8
Petersen, M B; Horisberger, M A; Warren, A C et al. (1989) Two PstI DNA polymorphisms adjacent to the human gene for the interferon-induced p78 protein (MX1 gene). Nucleic Acids Res 17:7546
Warren, A C; Slaugenhaupt, S A; Lewis, J G et al. (1989) A genetic linkage map of 17 markers on human chromosome 21. Genomics 4:579-91
Warren, A C; Groner, Y; Antonarakis, S E (1988) A DNA polymorphism with KpnI of the human liver-type phosphofructokinase (PFKL) gene. Nucleic Acids Res 16:9060
Antonarakis, S E; Oettgen, P; Chakravarti, A et al. (1988) DNA polymorphism haplotypes of the human apolipoprotein APOA1-APOC3-APOA4 gene cluster. Hum Genet 80:265-73

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