Ramsay M, Williamson R, Estivill X, Wainwright B J, Ho M F, Halford S, Kere J, Savilahti E, de la Chapelle A, Schwartz M
Department of Biochemistry and Molecular Genetics, St. Mary's Hospital Medical School, London, UK.
Hum Mol Genet. 1993 Jul;2(7):1007-14. doi: 10.1093/hmg/2.7.1007.
Positional cloning involves first finding linkage between an inherited phenotype (such as a disease) and a DNA marker, followed by the use of a variety of physical and genetic mapping techniques to move from linkage to mutation. If there is a founder effect within a population, crossovers are often rare between the mutation causing the phenotype and closely situated markers and increasing disequilibrium may be observed as the site of the mutation is approached. Standard coefficients of disequilibrium may, however, be insensitive to the relative position of close markers and the mutation, because they depend upon allele frequencies in the normal population compared to those of the founder chromosome. Using cystic fibrosis in European populations as a model system, alternative methods for determining the position of a mutation are discussed. These include haplotype parsimony and three-way interval likelihood analysis. Both methods predict the location of the major CF mutation accurately from a real set of more than 600 European CF chromosomes.
定位克隆首先涉及寻找遗传表型（如疾病）与DNA标记之间的连锁关系，随后运用各种物理和遗传图谱技术，从连锁关系过渡到突变的确定。如果群体中存在奠基者效应，那么在导致该表型的突变与紧密相邻的标记之间，交叉现象往往很少见，并且随着接近突变位点，可能会观察到不平衡现象加剧。然而，标准不平衡系数可能对紧密标记与突变的相对位置不敏感，因为它们取决于正常群体中的等位基因频率与奠基者染色体上的等位基因频率的比较。以欧洲人群中的囊性纤维化为模型系统，讨论了确定突变位置的替代方法。这些方法包括单倍型简约法和三方区间似然分析。两种方法都能从一组真实的600多条欧洲囊性纤维化染色体中准确预测主要囊性纤维化突变的位置。
