LINKAGE ANALYSIS OF CYSTIC FIBROSIS

该项目的目的是将当前的方法应用于检测和 多态遗传标记在囊虫连锁分析中的应用 尤其是信息丰富的家庭中的纤维化。该项目涉及一个 由L.O.Cavalli-Sforza指导的实验室与 玛丽-克莱尔·金为了找到和抽样足够的家庭和 调查足够数量的多态DNA和蛋白质标记。这个 该项目的具体目标是：(1)特别选择家庭 为囊性纤维化的连锁研究提供信息；(2)筛查所有 现有的多态DNA和蛋白质标记，目的是定位 标记相当小距离内的囊性纤维化基因(Cf) 如果成功，则寻找新的多态标记 更接近cf。 通过应用目前在DNA水平上检测多态的技术 对于囊性纤维化的基因分析，现在原则上是可能的， 以精确定位人类基因组上的cf。然而，非常大的数字 获得足够的连锁信息所需的标记和家系的数量 蛋白质产物未知的隐性疾病基因的分析 似乎使这样的努力不切实际。为了进行连锁分析 囊性纤维化的可行性，这个项目将利用两个技巧 抽样设计和实验室技术。首先，研究样本将 包括至少有两个在世儿童和受影响儿童的家庭 提供家长服务。这样的家庭包括大约七倍于 有一名受影响儿童和一名未受影响儿童的家庭的信息 甚至比只有一个的非常大的兄弟会有更多的信息 受影响的孩子。第二，筛选可能与cf相关的DNA标记。 将使用多个探针和混合物，以便最多10个多态 可以同时进行分析。这些功能将减少 测试次数足够多，建议定位cf是合理的 在相对较短的时间内以相当高的精度。 找到一个合理接近cf的遗传标记可以使产前 高危家族囊性纤维化的诊断和检测 这些家庭中的携带者。

The purpose of this project is to apply current methods for detection and analysis of polymorphic genetic markers to linkage analysis of cystic fibrosis in especially informative families. The project involves a collaboration between the laboratories directed by L.O. Cavalli-Sforza and Mary-Claire King in order to locate and sample sufficient families and survey an adequate number of polymorphic DNA and protein markers. The specific aims of the project are: (1) to select families especially informative for linkage studies of cystic fibrosis; (2) to screen all available polymorphic DNA and protein markers, with the aim of locating the cystic fibrosis gene (cf) within a reasonably small distance of a marker locus; and (3) if this is successful, to look for new polymorphic markers closer to cf. By applying present techniques for detecting polymorphisms at the DNA level to genetic analysis of cystic fibrosis, it is now possible, in principle, to precisely locate cf on the human genome. However, the very large number of markers and families required to obtain adequate information for linkage analysis of a recessive disease gene whose protein product is unknown would seem to make such an effort impractical. In order to make linkage analysis of cystic fibrosis feasible, this project will exploit two tricks of sampling design and laboratory technique. First, the study sample will include only families with at least two living, affected children and both parents available. Such families include about seven times as much information as families with one affected and one unaffected child and considerably more information than even very large sibships with only one affected child. Second, screening for DNA markers potentially linked to cf will employ multiple probes and mixtures so that up to ten polymorphisms can be analyzed simultaneously. These features will reduce the total number of tests sufficiently that it is reasonable to propose locating cf with considerable precision in a relatively short time. Finding a genetic marker reasonably close to cf could enable prenatal diagnosis of cystic fibrosis in families at high risk and detection of carriers in such families.