Pigmentary variation is an established and productive model genetic system for investigating basic biological processes relevant to human disease. Most of this work has been based on previously existing mouse coat color mutations, several of which are homologous to different forms of human albinism. However, mouse coat color mutations sample only a portion of pigmentary variation, because the processes and genes that control hair color are at least partially distinct from those that control skin color. ? ? In preliminary studies, we have developed a new model system for mammalian genetics based on mouse skin color. From about 30,000 animals subjected to a global screen for dominant phenotypes, we have focused on a novel class of pigmentation mutants identified by dark skin (Dsk). We determined the genetic map location, homozygous phenotype, and histological determinants of 10 new Dsk mutations, and identified missense alterations in Gnaq (Dsk1), Keratin2e (Dsk2), Egfr (Dsk5), and Gna11 (Dsk7). The Dsk mutations represent genes or genetic map locations not previously implicated in the pigmentary system, and delineate a multi-step developmental pathway in which genetic lesions can be classified based on the body region, microscopic site, and timing of pigment accumulation. ? ? We propose to further investigate the molecular and cellular basis for dark skin in mice by developing methods to trace the lineage and measure profiles of gene expression for different subsets of developing pigment cells, by determining the molecular identification and mechanism of action for the remaining Dsk mutations, and by expanding the Dsk screen to include additional dominant and recessive mutations. ? ?
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