A high-density molecular genetic map around the weaver locus

The weaver (wv) mutant is an animal model for abnormal cerebellar development. The mutation arrests granule cell differentiation, which results in a smaller cerebellum with a disorganized laminar structure and in ataxia. Weaver heterozygotes are not ataxic, but the laminar structure of their cerebellum is slightly disorganized, indicating that the weaver mutation acts in a semidominant fashion. The single allele of the weaver mutation arose spontaneously on the C57BL/6J background but is now maintained on a BL6CBAF sub(1)/J hybrid background. The locus was mapped to Chromosome (Chr) 16 initially by linkage to the dwarf (dw) mutation and was delimited to a 3.9-cM area by an intersubspecific backcross. For cloning of the weaver gene by positional mapping methods, two different backcrosses were initiated. In the process, 10 simple sequence length polymorphic (SSLP) markers that map to the region were ordered with respect to each other and the weaver locus. Differences in recombination frequencies between the markers owing to background and sex were examined. While analyzing our cross, a candidate for the weaver gene was identified. A single base pair change in GIRK2, a G protein-gated inwardly rectifying K super(+) channel-2, was reported. To investigate further whether GIRK2 is the weaver gene, we have mapped GIRK2 on our backcross. Other crosses and positional cloning efforts have demonstrated that recombination does not occur randomly along the chromosome and can vary between strains, so in an attempt to evenly distribute the crossover events, two different crosses were performed. Female weaver heterozygotes (B6CBACa-A super(w-J)/A-wv) were mated to males from the Mus molossinus (MOLD/Rk) and Mus castaneus (CAST/Ei) strains. Male and female F sub(1) progeny were then mated to C57BL/6J mice. +/wv were used in the cross because they breed better than the wv/wv homozygotes. From each N sub(2) mouse at postnatal day 30, the tail and liver were saved as a source of DNA, and the brain was dissected to determine the weaver phenotype. Since +/wv do not have a behavioral phenotype, there was no way of determining whether the F sub(1) mice were +/+ or +/wv until we examined the cerebella of their N sub(2) progeny. If the entire litter of N sub(2) mice were wild type, then it was assumed that the F sub(1) was +/+, and no further N sub(2) litters were analyzed. If at least one of the N sub(2) progeny from a litter was + /wv, then the F sub(1) must be +/wv, and subsequ