GENETIC DISEASES ASSOCIATED WITH CHROMOSOME 21

这项建议的目的是进行三项有关的研究， 21号染色体的分子遗传学 1.涉及染色体的DNA序列的表征 断裂和环形成。 我们鉴定了一个2.1kb的EcoRI片段 （命名为231 C），其定位于21号染色体环的断点 [r21（p13q22.3）]。 在这一区域的DNA克隆和测序后， 正常的21和r21染色体，我们将确定相关的序列 伴随着染色体的断裂和重组，我们将更好地理解 环形成的病理生理机制。 2.染色体DNA序列连锁图的构建 21. 该连锁图将包括几个单拷贝DNA片段， 超氧化物歧化酶基因（SOD-1）和同型胱氨酸尿症表型， 胱硫醚β合酶（CBetaS）缺乏。 3.检验某些21号染色体具有增加的 倾向于经历不分离（NDJ），因此产生Down 综合征（DS）。 使用单倍型分析四个不同的非常密切的 连锁DNA多态性位点，其映射到近端长臂， 我们在希腊人群的一项初步研究中证明了21号染色体 一条特定的21号染色体通常与NDJ有关。 进一步 对这一现象的研究将至少在一个以上的族裔中进行， 与希腊人没有血缘关系的群体。 DNA多态性标记 与单拷贝21号染色体特异性着丝粒序列相邻， 用于进一步表征目标染色体21。 分子 不同类型的21号染色体的DNA的克隆， NDJ的风险可能揭示了基因组的重要信息， DNA在“粘性”染色体中的组织。

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.