The availability of a complete genetic linkage map of the mouse consisting of DNA polymorphisms substantially increases the power of molecular genetics in the mouse: (i) since hundreds of genetic markers can be scored in a single cross, it is straightforward to undertake high-resolution linkage mapping of single gene traits and it is feasible to carry out genetic dissection of polygenic traits into discrete Mendelian factors (as has recently been done in several plant species); and (ii) since the genetic markers are defined by cloned DNA fragments, they can be used as starting points for chromosomal walks to clone genes on the basis of their genetic location even when no protein product is known (as has recently been done for cystic fibrosis in humans). One approach to constructing such linkage maps is to identify restriction fragment length polymorphisms (RFLPs) which differ between the laboratory mouse M. musculus and the wild mouse species M. spretus. Because the DNA sequences of the two species is sufficiently divergent, RFLPs are easily found. Recently, such interspecific crosses have been used to produce detailed linkage maps of the mouse. Such interspecific markers are useful for genetic mapping of cloned DNA fragments and mutations which ca be scored on an M. spretus background. Interspecific polymorphisms are not suitable, however, for scoring crosses between the various M. musculus inbred strains used for most experiments in genetics. Such crosses are essential for scoring the many mutants whose phenotype are substantially altered or obscured on an M. spretus genetic background, as well as for mapping polygenic variation in important physiological traits among M. musculus strains. Accordingly, we have been working on a procedure for isolating large numbers of polymorphisms among inbred M. musculus strains-based on screening Southern blots of denaturing gradient gels. An extensive pilot project demonstrates the effectiveness of this procedure. We propose to (1) fully develop this rapid procedure for detecting restriction fragment melting polymorphisms in mouse genomic DNA; (2) Identify and catalogue at least 300 polymorphisms among eight different mouse strains; and (3) map the polymorphisms by recombinational analysis.
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