DIFFERENTIAL EXPRESSION OF A NEW DOMINANT AGOUTI ALLELE (A(IAPY)) IS CORRELATED WITH METHYLATION STATE AND IS INFLUENCED BY PARENTAL LINEAGE

The agouti gene normally confers the wild-type coat color of mice. Dom inant mutations at the agouti locus result in a pleiotropic syndrome t hat is characterized by excessive amounts of yellow pigment in the coa t, obesity, a non-insulin-dependent diabetic-like condition, and the p ropensity to form a variety of tumors. Here, we describe a new dominan t mutation at the agouti locus in which an intracisternal A-particle ( IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named A(ia py), results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repe at (LTR). The coat color of A(iapy/)- mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and th e expressivity of this mutant phenotype varies with parental inheritan ce. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not diffe r from wild-type littermates. Data are presented to show that the diff erential expressivity of the A(iapy) allele is correlated with the met hylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequen ce that is responsible for the yellow coat color, obesity, diabetes, a nd tumorigenesis.