The relationship between induced mutation frequency and chromosome dosage in established mouse fibroblast lines

The frequencies of induced mutation to ouabain (OUA) and 6-thioguanine (6TG) resistance were compared in two established mouse fibroblast lines with different doses of the active X chromosome. The activity states of the X chromosomes were determined by DNA replication studies. Mutation frequency to 6TG R, an X-linked recessive phenotype, was inversely related to dosage whereas OUA R, a codominant phenotpye, occurred with equal frequency in both lines. 6TG R clones isolated from the line containing a majority of cells with two active X chromosomes were monosomic for the active X chromosome. Enzyme activity studies of these cytologically monosomic lines yieled results that were consistent with the presence of a single active X chromosome. The findings strongly support the hypothesis that mutation frequency is dependent on gene dosage.