Chapter 12

Microphthalmia and Other Considerations

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IV. Mutation Rates

Although some genes of the mouse seem more unstable than others, to estimate their relative mutation rates requires the surveillance of a large breeding colony over an extended period. It is scarcely surprising, therefore, that one of the most comprehensive studies on the frequency of occurrence of spontaneous mutations was carried out at the Jackson Laboratory between 1963 and 1669 (Schlager and Dickie, 1966, 1967, 1971). Of special interest to us is the fact that it included a number of coat color determinants, paying particular attention to the spontaneous mutation rates, both forward and reverse, at the agouti ( a), brown ( b), albino ( c), dilute ( d) and leaden (ln) loci. The number of mutations that were observed at these loci, along with their calculated mutation rates and 95% confidence limits ( Stevens, 1942), are presented in Table 12-5. Attention is drawn to the following:

  1. The overall spontaneous mutation rates were 11 x 10-6 per locus per gamete for mutations from wild type (forward mutations) and 2.5 x 10-6 for mutations from recessive alleles (reverse mutations). The 95% confidence limits of these two estimates do not overlap.
  2. A and C had relatively high mutation rates while the rates of a and d were higher than b, c, and ln. Indeed, b and c appear to be very stable since no mutations occurred in over 3 million opportunities. 29
  3. The only actual example of a forward and reverse mutation at the same locus occurred at the d-locus where D mutated to d (at a rate of 1.2 x 10-6) and d mutated to D (at a rate of 3.9 x 10-6). 30
  4. Of the five specific loci studied the highest rate of spontaneous mutation from wild type was recorded for the agouti locus, an observation which contrasts with the low mutation rate recorded for this locus under acute spermatogonial X-irradiation. Thus W. Russell and L. Russell ( 1959) observed only 2 mutations out of a total of 174 under dosages ranging from 300 to 1000 rad, and Lyon and Morriss ( 1966) found no a-locus mutations in over 16,000 offspring sired by males whose hind quarters had been exposed to 600 rad. Indeed, when one compares the spontaneous mutation rates of the a, b, c, and d-loci, as recorded by Schlager and Dickie, with those of the Russells' irradiation study, there appears to be an inverse relationship between the two rates in rank order: a > c > d > b for spontaneous mutations and b > d > c > a under irradiation. The basis for this relationship, if in fact it is a real one, remains to be elucidated.
  5. The results noted in Table 12-5 are in general accord with previous estimates of spontaneous mutation rates in mice. Thus the 95% confidence limits (7.3-16.6 x 10-6) of Schlager and Dickie's results encompass the 7.5 x 10-6 per locus per gamete spontaneous forward mutation rate cited by W. Russell ( 1963) for seven loci, including the a, b, c, d, p, and s loci, and the 10 x 10-6 forward mutation rate reported by Carter et al. ( 1958) for these same loci. 31

Schlager and Dickie also observed some spontaneous dominant coat-color mutations and have estimated the mutation rates at the loci involved ( Table 12-6). Again it is obvious that there are differences.

Of considerable interest also is Schlager and Dickie's ( 1967) observation that the incidence of spontaneous mutations appears to vary greatly from strain to strain ( Table 12-7). For example, of 18 W locus mutations, 10 occurred in the C57BL/6J strain and 3 appeared in the C3H/HeJ strain. The mutation rates of the W-locus in these two strains are therefore considerably higher than in other nonalbino strains. The C57BL/6J strain also displays a high incidence of reverse mutation at the a-locus, from a to at and to Aw (see Chapter 2, note 14). Indeed, the high frequency of mutations in the C57BL/6J strain raises the possibility that one or more mutator genes, i.e., genes though to produce a substance that induces transition mutants, are involved. Such genes are believed to occur in maize ( McClintock, 1951), Drosophila ( Demerec, 1937; Ives, 1950) and Salmonella ( Kirchner, 1960). 32

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