Detectable mutation rate

The spectrum of mutational effects runs the gamut of bodily processes. Genes affect all structures and functions, and so do mutations. The impact ranges from trivial to tragic. Depending on the dominance and severity of a mutation, its effect may be immediate or spread over an enormous period. It is therefore impossible to describe in detail or to quantify all the consequences of an increase in the mutation rate. One generalization is apt, however the net effect of an increase in mutation rate is harmful, because almost all mutants with any detectable effect cure deleterious. 

One possibility is that there is differential susceptibility to both mutation and killing among the cells. If, for example, there are two populations of cells, the high-dose data reflect the mutation rate of the component more resistant to killing. If these cells are also resistant to mutation, the resistance of the total cell population is underestimated. Another possibility is that there is a mutation-repair mechanism that is turned on at high doses. Deviations from either of these causes can usually be detected by the shape and slope of the curve at high doses for example, linear extrapolation from high-dose... 

About 7,000 F2 cultures are required to determine whether the spontaneous rate was at least doubled by the treatment. Obviously, fewer tests cure needed for mutagens that induce very large mutation rates. If a significant increase in recessive-lethal frequency has not been observed in 7,000 tests of the treated group, the treatment is considered to be negative. Finally, it should be stressed that, with 800 different test genes distributed over the X chromosome, unique DNA-mutagen specificities should be detectable. 

If the mutation rate increases by, say, 50%, it is likely, with the rapid increases in genetic knowledge, that methods to detect this will be developed within 30 yr. If not, these kinds of calculations cam easily be extended to a mutation increase of longer duration. 

This system therefore offers the possibility of detecting somatic mutations through selection in lymphocyte cultures. However, the extent to which some variations are phenocopies, rather than mutations, remains to be explored. Recent and more refined experiments have given much lower mutation rates, more consistent with other estimates.14142 The variables that influence the results remain to be elucidated, but the possibility of measuring mutation in somatic cells and documenting the nature of the mutant cells makes this a promising system. 

The second explanation is that the numbers of progeny examined in the tests were too small to permit detection of modest mutagenic responses. Hie historical spontaneous-mutation frequency in male mice is about 0.000058 per seven loci, so a test that examined 10,000 progeny from treated males and revealed no mutants would be unable to exclude, at the 95% confidence level, a total mutation rate less than 5 times the spontaneous rate. For an explanation of this calculation, see the appendix to Chapter 6. 

Although the subject is in its infancy, it is already clear that a substantial fraction, possibly a majority, of spontaneous mutations in Drosophila have such a cause. If that turns out to be true and generalizable to mammals (there is reason to believe that such elements are present in mice and humans), it will require a revision in our thinking about mutation and mutagens, and it would mean that the kinds of mutagenic mechanisms discussed in this report account for only a part of the spontaneous-mutation rate. On the one hand, we can conclude optimistically that classical mutagens are relatively less important. On the other hand, we cam assume pessimistically that chemicals not detectable with existing test systems increase the rate of transposon-induced mutations. 

Only germ cell mutations affect subsequent generations, 2, Most mutations are harmful, 3, Any increase in the mutation rate is by its nature difficult to detect, 4. Mild genetic effects are more numerous than severe effects, 5, Recessive mutations may remain in a population for hundreds of generations (Crow 1971a 22-23). 

The wide differences in the mutation rate inherent in these disorders govern the efforts of national associations of patients affected by lipidoses and that of enzyme replacement therapeutic industries. In turn, the clinical everyday practice triggers campaigns for the detection by genotyping combined with biochemical lipidomic methods which establish the screening efficiency in neonates. The history of cholesterol deficits such as the Smith-Lemli-Opitz... 

SNPs and InDei (Insertion/deletion) are distributed equally over the total genome of animals, plants, fungi, and bacteria. They have very low mutation rates and therefore can be used for animal or plant species determination, identification of fungi or bacterial strains, proof of identity, and authenticity testing. Detection of SNPs can be carried out on both genomic and mitochondrial DNA. 

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