Dominant cataract mutations and specific-locus mutations in mice induced by radiation or ethylnitrosourea

Abstract

In a combined experiment, dominant cataract mutations and specific-locus mutations were scored in the same offspring. In radiation experiments, a total of 15 dominant cataract and 38 specific-locus mutations was scored in 29396 offspring. In experiments with ethylnitrosourea (ENU), a total of 12 dominant cataracts and 54 specific-locus mutations was observed in 12712 offspring. The control frequency for dominant cataracts was 0 in 9954 offspring and for specific-locus mutations 11 in 169955 offspring. The ratio of radiation-induced recessive visible to dominant mutations was about 2.5:1. The difference was even more pronounced for ENU-induced mutations. The ratio of recessive visibles to dominant cataracts for chemically induced mutations in spermatogonia was about 5.4:1. The two characteristic features of radiation-induced specific-locus mutations— the augmenting effect of dose fractionation and the quantitative differences in the mutation rates between spermatogonial and post-spermatogonial stages — can also be demonstrated for the induction of dominant cataracts. The dominant cataract mutations recovered can be categorized into 7 phenotypic classes: total opacity, nuclear and zonular cataract, nuclear cataract, anterior pyramidal cataract, anterior polar cataract, anterior capsular cataract, and vacuolated lens. The largest class of mutations, a total of 11, affected the anterior polar region, while the number of total opacities in both experiments was 5. The only noteworthy difference observed between the radiation- and ENU-induced mutations recovered was that, of the 2 radiation-induced total lens opacities, both were associated with an iris anomaly and microphthalmia whereas the ENU-induced total opacities were not. Mutations at all 7 specific loci were observed in these experiments after exposure of spermatogonia to radiation or ENU. ENU induced twice as many mutations at the p locus and 3 times as many mutations at the d locus as did radiation. In contrast, ionizing radiation induced 4 times more mutations at the s locus than ENU. Double mutants ( d- se) were observed only in radiation experiments. These observations support our earlier conclusions that chemically induced DNA lesions in spermatogonia and the resultant mutations are different from those induced by radiation. The advantage of a large sample of induced dominant defects in one body system for the direct estimation of the genetic risk to the human population is discussed.