MOLECULAR-BASIS OF THE PLEIOTROPIC PHENOTYPE OF MICE CARRYING THE HYPERVARIABLE YELLOW (A(HVY)) MUTATION AT THE AGOUTI LOCUS

The murine agouti locus regulates a switch in pigment synthesis betwee n eumelanin (black/brown pigment) and phaeomelanin (yellow/red pigment ) by hair bulb melanocytes. We recently described a spontaneous mutati on, hypervariable yellow (A(hvy)) and demonstrated that A(hvy) is resp onsible for the largest range of phenotypes yet identified at the agou ti locus, producing mice that are obese with yellow coats to mice that are of normal weight with black coats. Here, we show that agouti expr ession is altered both temporally and spatially in A(hvy) mutants. Ago uti expression levels are positively correlated with the degree of yel low pigmentation in individual A(hvy) mice, consistent with results fr om other dominant yellow agouti mutations. Sequencing of 5' RACE and g enomic PCR products revealed that A(hvy) resulted from the integration of an intracisternal A particle (IAP) in an antisense orientation wit hin the 5' untranslated agouti exon 1C. This retrovirus-like element i s responsible for deregulating agouti expression in A(hvy) mice; agout i expression is correlated with the methylation state of CpG residues in the WP long terminal repeat as well as in host genomic DNA. In addi tion, the data suggest that the variable phenotype of A(hvy) offspring is influenced in part by the phenotype of their A(hvy) female parent.