VERNE CHAPMAN LECTURE: WILD MICE AS A SOURCE OF GENETIC POLYMORPHISM
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The founder colony of modern inbred laboratory strains was, most probably, a very small sized hybrid population derived from progenitors of the Mus musculus complex of species. This fact is substantiated by historical records as well as by the observation that most of the classical strains share the same mitochondrial DNA of Mus musculus domesticus origin and that most strains carry a Y chromosome from the Mus musculus musculus species. It follows that the genetic polymorphism present in these strains is not abundant and originates from three species: Mus m. domesticus, Mus m. musculus or Mus m. castaneus. Such a restricted genetic pool together with the relatively short period that has elapsed since the construction of present-day laboratory strains explains why such mice exhibit relatively little allelic variation compared, for example, with man. This disadvantage was overcome when mouse geneticists decided to take advantage of the diversity existing among wild specimens of the Mus genus, to develop new inbred strains what allowed the establishment of highly polymorphic inter-specific or inter-subspecific crosses. Except in a few cases, in particular when t-haplotypes were segregating in the wild progenitors, most attempts at establishing such inbred strains have been successful with wild mice of the Mus musculus complex of species. With progenitors of the other species of the Mus genus, such as Mus spretus or Mus spicilegus, the derivation of new inbred strains has proven more difficult but scientists have succeeded on several occasions.
The use of inbred strains derived from wild specimens is particularly appropriate in the design of experimental crosses for positional cloning of mouse genes because this allows the establishment of high resolution, high density maps of the flanking regions. In addition to their value as a source of genetic polymorphism, wild mice also represent an invaluable source of morphological variations at the level of karyotype. In laboratory strains a very large variety of reciprocal translocations or inversions exist that are by-products of the many experiments made to evaluate radiation hazards. On the contrary, Robertsonian translocations, or centric fusions, are uncommon. However, this type of chromosomal variations is fairly common in wild populations of the Mus m. domesticus species. These naturally occurring rearrangements have been extensively used for the generation of a wide variety of monosomies and trisomies. They have also been used for the demonstration of chromosomal imprinting. They are also very useful tools for gene localisation by in situ hybridisation because they assist in the discrimination between paired chromosomes, something that is often difficult using the normal mouse chromosomal complement. It is no risky prediction to say that, in the future, the use of wild mice will expand to other fields than gene mapping or the study of genomic imprinting. They will certainly become an essential tool for the study of epistatic interactions and for studies about cancer predisposition or susceptibility to infectious diseases.