The Lethal Yellow Allele-associated Provirus Results in the Production of Chimeric Viral-host RNAs

The lethal yellow (Ay) mutation is the most dominant allele at the agouti locus of the mouse. Mice heterozygous for this allele have a yellow coat color, are genetically obese with an increased susceptibility to cancer, and have other metabolic derangements. Mice homozygous for Ay die early in embryogenesis, possibly because of a trophectoderm defect. The Ay mutation is distinguished from the many alleles described at the agouti locus in being associated with an endogenous provirus, designated endogenous ecotropic murine leukemia viral locus 15 (Emv-15). To obtain DNA sequences from regions close to or within the agouti locus, we have isolated the Emv-15 provirus and have found that the DNA sequences adjacent to the provirus are part of a mouse gene that is expressed in the same transcriptional orientation as the proviral genes. These mouse DNA sequences recognize two distinct size classes of RNA in various adult wild-type tissues including skin. In Ay heterozygotes both types of transcript hybridize to the proviral long terminal repeat, and, in heterozygous spleens, the shorter transcript is present at an enhanced steady-state level. These results suggest that the Ay-associated provirus (Emv-15) is distinguished from the endogenous C-type proviruses described to date in having altered the expression of a flanking host gene by promoter insertion, resulting in the production of chimeric viral-host fusion transcripts.