FINE STRUCTURE GENETIC LINKAGE MAP OF CHROMOSOME 21 & 22

重组DNA技术的进步促进了这种增长 将连锁分析转化为一种强大的人类遗传学方法学 研究。所有染色体的遗传连锁图谱已经完成 使用数百个克隆基因和匿名DNA开发出来的 序列。这样的地图进一步增加了链接的力量 用于确定疾病基因位置的分析。然而，他们目前 实用性受到相当低的分辨率和不一致的限制 轨迹间距。 这项建议的目标是生成 人类21号和22号染色体，性别平均分辨率为1厘米。 将在包含1400多个数据的100个子船上生成数据 可能提供信息的减数分裂。具有分辨率的初始地图 略小于10厘米的已存在，并将用作 高分辨率地图的主干。探头将被获取 来自所有来源，包括COSMID库。与…相比 物理测绘结果(根据单独的建议生成)，a 可使用定向克隆策略来填补代表性不足 地区。用于错误检查和分析的高效方法 将显著减少计算机的时间 这是必要的。 由此产生的精细结构地图将是 和现在的地图一样精确。他们将大幅增加 任何疾病基因驻留在这两个基因上的效率 染色体可以被定位，并将提供良好的起点 疾病基因座直接克隆的要点。统计 对数据的分析将有助于回答以下问题 重组的变异因性别、年龄、种族背景和 家族聚集性。它还将有助于确定 干扰的适当参数。产前和 疾病的症状前诊断将成为可能，而且准确无误 几乎完全依赖于家系结构和临床 诊断，而不是在测试的标记物上。最后，这些地图将 允许在物理图谱和基因图谱之间进行信息性比较， 提供了对染色体结构和组织的新见解， 并促进了对21号和22号染色体的最终测序。

Advancements in recombinant DNA technology have nurtured the growth of linkage analysis into a powerful methodology for human genetic research. Genetic linkage maps of all the chromosomes have been developed using hundreds of cloned genes and anonymous DNA sequences. Such maps further increase the power of linkage analysis to define disease gene location. However, their current utility is limited by rather low resolution and inconsistent spacing of loci. The goal of this proposal is to generate genetic linkage maps of human chromosomes 21 and 22 with a sex-averaged resolution of 1 cM. Data will be generated on 100 sibships containing over 1400 potentially informative meioses. Initial maps with resolutions slightly less than 10 cM already exist and will serve as the backbone for the high resolution maps. Probes will be obtained from all sources, including cosmid libraries. By comparison with physical mapping results (generated under separate proposals), a directed cloning strategy may be used to fill under-represented regions. Efficient methodologies for error checking and analysis of the data will significantly reduce the amount of computer time necessary. The resulting fine-structure maps will be five to ten times as precise as current maps. They will substantially increase the efficiency with which any disease gene residing on these two chromosomes can be localized, and will provide excellent starting points for direct cloning of the disease gene locus. Statistical analysis of the data will help answer questions concerning variation in recombination by sex, age, ethnic background, and familial clustering. It will also aid in the determination of appropriate parameters for interference. Prenatal and presymptomatic diagnosis of disease will be possible with accuracy almost totally dependant on the pedigree structure and clinical diagnosis, not on the markers tested. Finally, these maps will allow informative comparisons between physical and genetic maps, providing new insights into chromosome structure and organization, and facilitating the eventual sequencing of chromosomes 21 and 22.