A MOLECULAR-MODEL FOR THE GENETIC AND PHENOTYPIC CHARACTERISTICS OF THE MOUSE LETHAL YELLOW (A(Y)) MUTATION

Lethal yellow (A(y)) is a mutation at the mouse agouti locus in chromosome 2 that causes a number of dominant pleiotropic effects, including a completely yellow coat color, obesity, an insulin-resistant type II diabetic condition, and an increased propensity to develop a variety of spontaneous and induced tumors. Additionally, homozygosity for A(y) results in preimplantation lethality, which terminates development by the blastocyst stage. The A(y) mutation is the result of a 170-kb deletion that removes all but the promoter and noncoding first exon of another gene called Raly, which lies in the same transcriptional orientation as agouti and maps 280 kb proximal to the 3' end of the agouti gene. We present a model for the structure of the A(y) allele that can explain the dominant pleiotropic effects associated with this mutation, as well as the recessive lethality, which is unrelated to the agouti gene.