ISOLATION OF CHROMOSOME 21 GENES AND CHARACTERIZATION IN THE MOUSE

唐氏综合症的主要表型方面包括智力低下， 白血病、心脏和肠道缺陷、免疫缺陷和阿尔茨海默氏症 疾病。人类21号染色体上的未知数量的基因是 当唐氏综合症出现在三份复印件时，负责。 在可能位于染色体上的500-1000个基因中，只有不到24个 21个已被克隆和鉴定。因此，我们没有一个 足够数量或种类的可供选择的基因 唐氏综合征谱系的可信和引人注目的候选基因 功能。 我们使用了21号染色体的物理和表型图谱来选择 可能包含的区域和克隆(YAC、Cosmids和lambda 相关基因。我们建议：i)分离编码 转录因子和细胞表面标记，使用DNA序列基序 和组织特异性抗体，ii)从该区域分离基因 在D21S55周围跨越大约3 MBP，因为这个区域是 可能涉及许多最关键的医学特征，III) 在21q21寻找新的基因，因为这个区域与 阿尔茨海默病。 为了确定这些基因的特征，我们建议：i)分析序列 通过GenBank和Grail提供的信息，II)确定组织特异性 以及在人类和小鼠胚胎中表达的发育时间， 胎儿和成人组织，以及iii)使用小鼠部分三体16模型 系统，以确定剂量效应和组织定位。基于 这些信息，我们将选择被认为最有可能相关的基因 唐氏综合症，并开始蛋白质特征分析。 这项建议的最终目的是增加我们对 发育事件的基因水平，因为它们适用于唐氏综合症。在……里面 在这个过程中，我们将产生一个具有良好特性的基因集合 其中用于创造转基因的多基因构建物可以 最终会被开发出来。

The major phenotypic aspects of Down Syndrome include mental retardation, leukemia, heart and gut defects, immune deficiencies, and Alzheimer's Disease. An unknown number of genes on human chromosome 21 are responsible for Down Syndrome when they are present in three copies. Fewer than 2 dozen of the probably 500-1000 genes located on chromosome 21 have been cloned and characterized. As a result, we do not have a sufficient number or variety of genes from which to choose the most credible and compelling candidate genes for the spectrum of Down Syndrome features. We have used the physical and phenotypic map of chromosome 21 to choose regions and clones (YACs, cosmids and lambda) that are likely to contain relevant genes. We propose to: i) isolate genes coding for transcription factors and cell surface markers, using DNA sequence motifs and tissue specific antibodies, ii) isolate genes from the region spanning approximately 3 mbp surrounding D21S55, because this region is likely involved in many of the most medically critical features, iii) search for new genes in 21q21, because this region is associated with Alzheimers Disease. To characterize these genes, we propose to: i) analyze sequence information through GenBank and Grail, ii) determine tissue specificity and developmental timing of expression in human and mouse embryonic, fetal and adult tissue, and iii) use a mouse partial trisomy 16 model system to determine dosage effects and tissue localization. Based on this information, we will choose genes judged most likely to be relevant to Down Syndrome, and begin protein characterization. The ultimate aim of this proposal is to increase our understanding at the gene level of developmental events, as they apply to Down Syndrome. In the process, we will generate a well characterized collection of genes from which multigene constructs for the creation of transgenic can eventually be developed.