OPPOSITE ORIENTATIONS OF AN INVERTED DUPLICATION AND ALLELIC VARIATION AT THE MOUSE AGOUTI LOCUS

The mouse agouti protein is a paracrine signaling molecule that causes yellow pigment synthesis. A pale ventral coloration distinguishes the light-bellied agouti (A(W)) from the agouti (A) allele, and is caused by expression of ventral-specific mRNA isoforms with a unique 5' untr anslated exon. Molecular cloning demonstrates this ventral-specific ex on lies within a 3.1-kb element that is duplicated in the opposite ori entation 15-kb upstream to produce an interrupted palindrome and that similarity between the duplicated elements has been maintained by gene conversion. Orientation of the palindrome is reversed in A compared t o A(W), which suggests that mutation from one allele to the other is c aused by intrachromosomal homologous recombination mediated by sequenc es within the duplicated elements. Analysis of 15 inbred strains of la boratory and wild-derived mice with Southern hybridization probes and closely linked microsatellite markers suggests six haplotype groups: o ne typical for most strains that carry A(W) (129/SvJ, LP/J, CE/J, CAST /Ei), one typical for most strains that carry A (Balb/cJ, CBA/J, FVB/N , PERA/Rk, RBB/Dn); and four that are atypical (MOLC/Rk, MOLG/Dn, PERA /Ei, PERC/Ei, SPRET/Ei, RBA/Dn). Our results suggest a model for molec ular evolution of the agouti locus in which homologous recombination c an produce a reversible switch in allelic identity.