Justice M J, Noveroske J K, Weber J S, Zheng B, Bradley A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77096, USA.
Hum Mol Genet. 1999;8(10):1955-63. doi: 10.1093/hmg/8.10.1955.
The progress of human genome sequencing is driving genetic approaches to define gene function. Strategies such as gene traps and chemical mutagenesis will soon generate a large mutant mouse resource. Point mutations induced by N -ethyl- N -nitrosourea (ENU) provide a unique mutant resource because they: (i) reflect the consequences of single gene change independent of position effects; (ii) provide a fine-structure dissection of protein function; (iii) display a range of mutant effects from complete or partial loss of function to exaggerated function; and (iv) discover gene functions in an unbiased manner. Phenotype-driven ENU screens in the mouse are emphasizing relevance to human clinical disease by targeting cardiology, physiology, neurology, immunity, hematopoiesis and mammalian development. Such approaches are extremely powerful in understanding complex human diseases and traits: the base-pair changes may accurately model base changes found in human diseases, and subtle mutant alleles in a standard genetic background provide the ability to analyze the consequences of compound genotypes. Ongoing mouse ENU mutagenesis experiments are generating a treasure trove of new mutations to allow an in-depth study of a single gene, a chromosomal region or a biological system.
人类基因组测序的进展正在推动采用遗传学方法来确定基因功能。基因捕获和化学诱变等策略很快将产生大量的突变小鼠资源。由N-乙基-N-亚硝基脲（ENU）诱导的点突变为独特的突变资源，因为它们：（i）反映了单基因变化的结果，而不受位置效应的影响；（ii）对蛋白质功能进行精细结构剖析；（iii）表现出从功能完全或部分丧失到功能亢进的一系列突变效应；以及（iv）以无偏见的方式发现基因功能。在小鼠中进行的由表型驱动的ENU筛选，通过针对心脏病学、生理学、神经学、免疫、造血和哺乳动物发育，强调与人类临床疾病的相关性。此类方法在理解复杂的人类疾病和性状方面极其强大：碱基对变化可能准确模拟人类疾病中发现的碱基变化，并且标准遗传背景中的微妙突变等位基因提供了分析复合基因型后果的能力。正在进行的小鼠ENU诱变实验正在产生大量新的突变，以便对单个基因、染色体区域或生物系统进行深入研究。
