Mammalian mutagenesis: future directions.

Abstract

Future research in mammalian germ-line mutagenesis will benefit from the reciprocal relationship that can exist between the production of mutations and their analysis. Thus, mutagenesis experiments supply altered genes, and thereby tools for basic studies; while, in turn, information on gene structure and function helps in understanding mechanisms of mutagenesis. The nature of genetic alterations recovered in specific-locus tests is illustrated by an account of the analysis of 112 radiation-induced mutations involving the c locus on chromosome 7. Using phenotypic characterizations of various kinds, deficiency mapping with nearby markers, and complementation studies, the mutants could be classed into 13 groups, and 8 functional units could be identified in the c-locus region. Twelve different deficiencies overlapping at c range in length from less than 2 to 6-11 cM. Using the deficiencies, as well as a tandem duplication that involves the c region, and several T(X;7)'s in which c is inactivated in a mosaic fashion, it is possible to generate gene doses from 0 to 3, in steps of 0.5, not only for c but also for other genes included in various deficiencies. Cis and trans configurations can also be compared. This array of genetic materials is now being used for the isolation of DNA sequences from genetically-defined regions. Results from analyses of mutations can contribute answers to some of the pragmatic questions in germ-line mutagenesis and risk assessment. Areas in which contributions may be expected are: the relative roles of intracellular conditions (e.g., nature of chromatin, presence of repair enzymes) and secondary circumstances (e.g., selection) in determining the quantity and quality of transmitted mutations; the validity of quantitative extrapolations, such as projections to low doses and calculations of doubling dose; and the relation between measures of mutation rate and projections of phenotypic damage.