STRUCTURAL-ANALYSIS OF CHROMOSOMAL REARRANGEMENTS ASSOCIATED WITH THEDEVELOPMENTAL MUTATIONS PH, W-19H, AND RW ON MOUSE CHROMOSOME-5

We are studying the chromosomal structure of three developmental mutat ions, dominant spotting (W), patch (Ph), and rump white (Rw) on mouse chromosome 5. These mutations are clustered in a region containing thr ee genes encoding tyrosine kinase receptors (Kit, Pdgfra, and Flk1). U sing probes for these genes and for a closely linked locus,D5Mn125, we established a high-resolution physical map covering approximate to 2. 8 Mb. The entire chromosomal segment mapped in this study is deleted i n the W-19H mutation. The map indicates the position of the Ph deletio n, which encompasses not more than 400 kb around and including the Pdg fra gene. The map also places the distal breakpoint of the Rw inversio n to a limited chromosomal segment between Kit and Pdgfra. In light of the structure of the Ph-W-Rw region, we interpret the previously publ ished complementation analyses as indicating that the pigmentation def ect in Rw/+ heterozygotes could be due to the disruption of Kit and/or Pdgfra regulatory sequences, whereas the gene(s) responsible for the recessive lethality of Rw/Rw embryos is not closely linked to the Ph a nd W loci and maps proximally to the W-19H deletion. The structural an alysis of chromosomal rearrangements associated with W-19H, ph, and Rw combined with the high-resolution physical mapping points the way tow ard the definition of these mutations in molecular terms and isolation of homologous genes on human chromosome 4.