Towards an understanding of position effect variegation

Abstract Most variegating position effects are a consequence of placing a euchromatic gene adjacent to α‐heterochromatin. In such rearrangements, the affected locus is inactivated in some cells, but not others, thereby giving rise to a mosaic tissue of mutant and wild‐type cells. A detailed examination of the molecular structure of three variegating white mottled mutations of Drosophila melanogaster , all of which are inversions of the X chromosome, reveals that their euchromatic breakpoints are clustered and located approximately 25 kb downstream of the white promoter and that the heterochromatic sequences to which the white locus is adjoined are transposons. An analysis of three revertants of the w m4 mutation, created by relocating white to another euchromatic site, demonstrates that they also carry some heterochromatically derived sequences with them upon restoration of the wild‐type phenotype. This suggests that variegation is not controlled from a heterochromatic sequence immediately adjacent to the variegating gene but rather from some site more internal to the heterochromatic domain itself. As a consequence of this observation we have proposed a boundary model for understanding how heterochromatic domains may be formed. It has been recognized for many years that the phenotype of variegating position effects may be altered by the presence of trans ‐acting dominant mutations that act to either enhance or suppress variegation. Using P‐element mutagenesis, we have induced and examined 12 dominant enhancers of variegation that represent four loci on the second and third chromosomes. Most of these mutations are cytologically visible duplications or deficiencies. They exert their dominant effects through changes in the copy number of wild‐type genes and can be divided into two reciprocally acting classes. Class I modifiers are genes that act as enhancers of variegation when duplicated and as suppressors when mutated or deficient. Conversely, class II modifiers are genes that enhance when mutated or deleted and suppress when duplicated. The available data indicate that, in Drosophila , there are 20‐30 loci capable of dominantly modifying variegation. Of these, most appear to be of the class I type whereas only two class II modifiers have been identified so far. But how does a change in the dosage of only one of a large number of modifier loci act to enhance or suppress, in an antipodal manner, the variegating phenotype? If each of the class I genes is involved in the formation of heterochromatin, then changing the dosage of a single member of the group might not be expected to modify variegation since the dosage of any of the remaining members of that group should still be rate limiting. These remaining members appear to be rate limiting because each has a dose‐dependent effect on the phenotype as indicated by the fact that decreasing any one of them causes suppression of variegation. To explain this paradoxical behavior we propose a model, based on the law of mass action, for understanding how these suppressor‐enhancer loci function. The model assumes that each class I gene codes for a protein involved in the assembly of heterochromatic domains. From a consideration of this assembly reaction we show that, at equilibrium, the final concentration of assembled product varies as an exponential function of the concentration of each component of the reaction. The mass action model provides some insight into the dynamics and control of a repressed (heterochromatic) state as well as assembly‐driven reactions in general. Our results also have broader implications for a variety of antipodal dosage‐dependent effects, particularly as they relate to developmentally significant loci and the elaboration of developmental switches.