FINE STRUCTURE GENETIC LINKAGE MAP OF CHROMOSOME 21 & 22

重组DNA技术的进步促进了 将连锁分析转化为一种强大的人类遗传学方法 research. 所有染色体的遗传连锁图已经被 利用数百个克隆基因和匿名DNA 序列的 这样的地图进一步增加了联动的力量 分析以确定疾病基因定位。 然而，目前 实用性受限于相当低的分辨率和不一致性 基因座间距 这项建议的目标是产生遗传连锁图谱的 人类21号和22号染色体，性别平均分辨率为1 cM。 数据将在100个兄弟姐妹中产生，其中包含1400多个 可能提供信息的减数分裂。 带有分辨率的初始地图 略低于10厘米已经存在，并将作为 高分辨率地图的主干。 将获得探针 所有来源，包括粘粒库。 通过比较 实际测绘结果（根据不同的建议生成），a 定向克隆策略可用于填充代表性不足的 地区 错误检查和分析的有效方法 将大大减少计算时间 必要 由此产生的精细结构图将是 就像现在的地图一样。 它们将大大增加 任何存在于这两个基因上的疾病基因 染色体可以定位，并将提供良好的启动 用于直接克隆疾病基因位点的点。 统计 对数据的分析将有助于回答以下问题 性别、年龄、种族背景和 家族聚集 它还将有助于确定 适当的干扰参数。 产前和 疾病的症状前诊断将是可能的， 几乎完全依赖于谱系结构和临床 诊断，而不是测试的标志物。 最后，这些地图将 允许物理和遗传图谱之间的信息比较， 为染色体结构和组织提供了新的见解， 并有助于染色体21和22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.