White R L, Lalouel J M, Lathrop G M, Leppert M F, Nakamura Y, O'Connell P
West J Med. 1987 Oct;147(4):423-7.
Although a number of human genes that cause disease have been traced through the defective product, most genetic defects are recognized only by phenotype. When the biochemical defect is unknown, a gene can be located only through molecular approaches based on coinheritance (genetic linkage) of the disease phenotype with a particular allele of a polymorphic DNA marker that has already been mapped to a specific chromosomal region. Linkage studies in affected families have already localized genes for several important diseases, including cystic fibrosis. Finding a genetic linkage in families in which a disease segregates requires that the human genetic map have a large number of polymorphic markers; when the map is dense enough, any disease gene can be located by linkage to a known marker. Many DNA segments with a high degree of polymorphism are being found and mapped as markers in normal reference pedigrees. Genetic linkage mapping has implications even broader than its application to prenatal diagnosis or therapeutic strategy; analyzing mutations in important genes will illuminate basic mechanisms in molecular biology and the early events that lead to cancer and other disorders.
尽管通过缺陷产物已追踪到许多导致疾病的人类基因，但大多数遗传缺陷仅通过表型才能识别。当生化缺陷未知时，基因只能通过基于疾病表型与已定位到特定染色体区域的多态性DNA标记的特定等位基因的共遗传（遗传连锁）的分子方法来定位。在受影响的家族中进行的连锁研究已经定位了几种重要疾病的基因，包括囊性纤维化。在疾病发生分离的家族中发现遗传连锁需要人类遗传图谱有大量的多态性标记；当图谱足够密集时，任何疾病基因都可以通过与已知标记的连锁来定位。许多具有高度多态性的DNA片段正在被发现并作为正常参考谱系中的标记进行定位。遗传连锁图谱的意义甚至比其在产前诊断或治疗策略中的应用更为广泛；分析重要基因中的突变将阐明分子生物学的基本机制以及导致癌症和其他疾病的早期事件。
