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da: The specific locus test (Jackson Laboratory)

The experiments performed by Russell and Carter, and other colleagues who followed in their footsteps, were designed to obtain discrete values for the mutagenic potential of different radiation protocols. Rather than attempt to examine all animals for all effects of a particular irradiation protocol (as was common in earlier experiments), these mouse geneticists chose instead to look only at the small fraction of animals that were mutated at a small set of well-defined "specific" loci. The rationale for the "specific locus test" was that effects on individual loci could be more easily quantitated and that the limited results obtained could still be extrapolated for an estimate of whole genome effects. Russell decided that mutation rates should be followed simultaneously at a sufficient number of loci to distinguish and avoid problems that might be caused by locus-to-locus variations in sensitivity to particular mutagens. He decided further that the same set of loci should be examined in each experiment performed. The seven loci chosen to be followed in the specific locus test were defined by recessive mutations with visible homozygous phenotypes that were easily distinguished in isolation from each other, and had no effect on viability or fertility. The seven loci are agouti (a is the recessive non-agouti allele), brown (b), albino (c), dilute (d), short-ear (se), pink-eyed dilution (p), and piebald (s). A special "marker strain" was constructed that was homozygous for all seven loci.

In its simplest form, the specific locus test is carried out by mating females from the special marker strain to completely wild-type males that have been previously exposed to a potential mutagen. In the absence of any mutations, offspring from this cross will not express any of the seven phenotypes visible in the marker strain mother. However, if the mutagen has induced a mutation at one of the specific loci, the associated mutant phenotype will be uncovered. This test is very efficient because it only requires a single generation of breeding and visual examination is all that is required to score each animal.

Although recessive mutations at all loci other than the specific seven will go undetected in the first generation offspring from this cross, it is possible to detect a dominant mutation at any locus so long as it is viable and produces a gross alteration in heterozygous phenotype such as a skeletal or coat color change. One should realize that the most common effect of any undirected mutagen will be to "knock-out" a gene and, in the vast majority of cases, the resulting null allele will be recessive to the wild-type. There is, however, a very small class of loci at which null alleles will act in a dominant or semidominant fashion to wild-type. These "haplo-insufficient" phenotypes are presumably caused by a developmental sensitivity to gene product dosage. Among the best characterized of the dominant-null mutations are the numerous ones uncovered at the T locus — which result in a short tail — and the W locus — which result in white spotting on the coat.

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