Inbred Strains

These are produced by at least 20 generations of brother x sister mating or its genetic equivalent. For example, parent x offspring mating is one alternative, provided the mating is always to the younger of the two parents (several generations of mating female offspring to the same male is not the same thing, genetically). The effect of this mating scheme is to increase homozygosity within the strain to more than 98% (Figure 9.1), though the approach to complete homozygosity is asymptotic, and in theory, a strain never becomes fully inbred. All individuals within an inbred strain should also trace back to a single breeding pair in the 20th or a subsequent generation. This is to ensure that the strain is also isogenic (see below) by eliminating parallel substrains. Inbreeding also increases the total genetic and phenotypic variation, but all this variation is seen as differences between the substrains. Thus, if an outbred stock is inbred and all sublines are kept, the total phenotypic variation is substantially greater than in the original colony.

Properties of Inbred Strains

Inbred strains have been described as "immortal clones of genetically identical individuals," and as such, have many useful properties that make them the animal of choice, where they are available, for many types of research. The main properties of these strains are as follows:

1. Isogenicity — All animals within a strain are virtually genetically identical. One consequence is that only a single individual needs to be genotyped at any locus in order to type the whole strain. Over a period of time, a catalog or "genetic profile" of the alleles carried by each inbred strain can be accumulated. This information can be used in planning and interpreting experiments and in mapping genes of interest. Isogenicity also implies that a single male and female taken from the colony should have all the alleles present in that colony. Hence, a daughter colony founded on a single breeding pair will, for most practical purposes, be genetically identical to the parent colony, at least until the colonies begin to diverge as a result of the accumulation of new mutations (see below). Isogenic individuals will also be immunologically histocompatible, so that skin, cell, and organ grafts exchanged between same-sex members of the same strain should not be immunologically rejected.

2. Homozygosity — Inbred strains are defined in terms of homozygosity. By the end of 20 generations of full sibling mating, the chance that any two alleles at a given locus are identical by descent (i.e., are copies of the same allele in a previous generation) is more than 98%. The most important practical consequence of this is that there should be no genetic segregation within the strain, so all genes will be expressed under appropriate conditions, and there will be no hidden recessive genes, which could cause confusion in breeding experiments.

3. Phenotypic uniformity — As there is no genetic variation within an inbred strain, the phenotype for highly inherited characters tends to be more uniform. The only variation between individuals will be due to nongenetic causes. One consequence is that, other things being equal, fewer inbred animals will be needed to achieve a given level of statistical precision than if outbred animals had been used. In some cases, the use of isogenic animals can lead to substantial reductions in the estimated numbers of animals needed to do a particular experiment. Table 9.4 shows the mean and standard deviation of sleeping time under hexobarbital anesthesia in five inbred strains and two outbred stocks of mice33 and the estimated sample sizes that would be required in an experiment to detect a 4 min change in sleeping time as a result of some experimental manipulation. Note that this experiment could be done using an average of 18 inbred mice in each group or 244 outbred mice to achieve the same level of statistical precision. Clearly, for this reason alone, there is a strong case for using isogenic strains.

4. Long-term stability — In an outbred stock, change in allele frequency and, therefore, in phenotype, can be caused by directional selection, genetic drift due to inbreeding, and new mutations, assuming genetic contamination is avoided. An inbred strain is already fully inbred, so further inbreeding will have no effect. As there is no genetic variations within the strain, directional selection should be ineffective in changing the genotype and phenotype. Thus, the phenotype of an inbred strain will only change as a result of the fixation of new mutations or as a result of environmental changes (which can often be of great importance). New mutations are relatively rare, and only a quarter of them will normally be fixed with continued full sib mating, so inbred strains tend to stay genetically constant for quite long periods of time. Even the low amount of genetic drift due to new mutations can be eliminated by preserving frozen embryos. In a few cases, directional selection

Table 9.4 Sleeping Time Under Barbiturate Anesthetic in Five Inbred Strains and Two Outbred Stocks of Mice, and Number of Mice Estimated to be Needed to Detect a Change in Sleeping Time in an Experiment Involving Control Mice and Those Treated with a Compound Thought to Alter Sleeping Time

Strain

n

Mean

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