Genetic analysis of the hooded phenotype in the rat

The hooded phenotype showing non-pigmented hairs in the abdominal skin is one of the coat color phenotypes seen peculiarly in the laboratory rat. The hooded locus showing autosomal recessive inheritance has been mapped on Chr 14 and that the hooded phenotype receives modification by hooded-modifier gene showing linkage to the hooded locus. Thus, I have conducted genetic studies to identify a gene responsible for the hooded locus and genes responsible for hooded-modifiers. In part 1 of this study, I narrowed critical region of the hooded locus and revealed that only Kit gene, known as a marker of melanocyte and one of coat color genes, exists in this region through genetic fine mapping using backcrosses from feral rat-derived inbred strain IS and hooded phenotype strain, LEA. Although a G to C transversion was observed in exon 2 of the Kit gene, it was synonymous substitution. Further, the expressions of Kit mRNA were not different in fetal neural tubes and neonatal and adult skins between IS and LEA rats. Furthermore, Kit-positive cells were observed in LEA rat abdominal skin in spite of the absence of melanin in this region. These results suggest that the synthesis of melanin is impaired possibly due to the malfunction of Kit-expressed melanocytes residing in the non-pigmented hair follicles of hooded phenotype rats. However, substantial mutation of the Kit gene and the mechanisms by which Kit impairs the function of melanocytes in non-pigmented hair follicle remain unknown. In part 2 of this study, I carried out genetic linkage studies using BN and LEA rats to clarify genetic control in the extent of the hooded phenotype. A genome-wide scan was conducted on 152 F2 rats for linkage with ratio of pigmented coat area for the dorsal, ventral, and total regions. The result indicated that a major QTL was mapped to D14Got40, which is the microsatellite marker closely present to the hooded locus. In addition, another QTL, D17Rat2 showing highly significant linkage was also detected on Chr 17 in dorsal region phenotype as well as a QTL showing suggestive linkage on Chr15 in ventral region phenotype. I further investigated a genome-wide scan for epistatic interactions and detected significant interactions between D14Got40 and D20Mit1, and between D14Got40 and D17Rat2 in dorsal region phenotype. These results suggest that the hooded locus regulates the extent of the hooded phenotype with some modifier genes. This study proposes that Kit is a strong candidate gene responsible for the hooded locus and some genetic loci modify the extent of the hooded phenotype, although the precise mechanisms of them are still unclear. Thus, further study is necessary to understand the mechanisms by which the hooded phenotype appears with various extent of pigmented ratio in the rat.