GENETIC DISEASES ASSOCIATED WITH CHROMOSOME 21

这项建议的目标是进行三项相关的研究 21号染色体的分子遗传学。 1.与染色体有关的DNA序列的特征 断裂和环状形成。我们已经鉴定出一个2.1kb的EcoRI片段 (命名为231C)，它映射在21环染色体的断点处 [r21(p13q22.3)]。在这一区域的DNA克隆和测序之后，在两个 正常的21号染色体和R21号染色体，我们将鉴定相关序列 随着染色体的断裂和重聚，我们将更好地理解 环状形成的病理生理机制。 2.染色体DNA序列连锁图谱的构建 21.这个连锁图谱将包括几个单拷贝DNA片段， 超氧化物歧化酶基因(SOD-1)与同型半胱氨酸尿症 胱硫醚β合成酶(CBetaS)缺乏症。 3.对某些21号染色体有增加的假设的检验 倾向于经历不分离(NDJ)，因此产生向下 综合征(DS)。使用非常接近的四个不同的单倍型分析 连锁DNA多态位点，定位于长臂近端 我们在希腊人群中的一项初步研究中展示了21号染色体 一条特殊的21号染色体通常与NDJ有关。进一步 对这一现象的研究将在至少一个民族中进行。 与希腊人没有基因联系的群体。DNA多态标记 与单拷贝21号染色体相邻的特定着丝粒序列将 用来进一步确定目标染色体21的特征。分子 不同类型21号染色体DNA的克隆 NDJ的风险可能揭示关于基因组的重要信息 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.