Pleiotropy and the detection of point mutations in the mammal.

Several point mutations in the mouse profoundly affect the metabolic characteristics of the animal. As examples may be cited the "muscular dystrophy" mutation (dy), the "obese" and "diabetes" mutations (ob,db), the "yellow" mutations (AY,AVy,etc.) at the agouti locus, the two "pituitary dwarf" mutations (dw,df), and several mutations affecting body size, e.g., "pygmy" (pg) (1). In none of these cases has the polypeptide directly altered by the mutation yet been identified. In the case of the obese obob mutant the primary lesion remains unknown in spite of more than 20 years of effort by numerous investigators. Most "visible" mutations, such as those affecting coat color, eye color, and other morphological and neurological characteristics, also fall into this category of mutations in which the primary polypeptide lesion is unknown. The affected characteristics, in general, result from the interactions of many developmental processes and metabolic pathways. The mutations presumably alter polypeptides which are involved at branchpoints or critical rate-limiting steps in one or more of the interacting metabolic pathways. Thus the influence of these mutations is exerted at some point prior to the final definition of the particular characteristic by which each mutant is recognized. These considerations suggest that the majority of these muta-