The frequency and differential pleiotropy of phenotypic nonspecificity in Drosophila melanogaster

The regulation of the initiation of transcription by transcription factors is often assumed to be dependent on specific recognition of DNA-binding sites and nonredundant. However, the redundant induction or rescue of a phenotype by transcription factors, phenotypic nonspecificity, challenges these assumptions. To assess the frequency of phenotypic nonspecificity in the rescue of transcription factor phenotypes, seven transcription factor phenotypes (labial, Deformed, Sex combs reduced, Ultrabithorax, fruitless, doublesex, and apterous) were screened for rescue by the expression of 12, or more, nonresident transcription factors. From 308 assessments of rescue by nonresident transcription factors, 18 rescues were identified across 6 of the 7 transcription factor phenotypes. Seventeen of the 18 rescues were with transcription factors that recognize distinct DNA-binding sites relative to the resident transcription factors. All rescues were nonuniform across pleiotropic transcription factor phenotypes suggesting extensive differential pleiotropy of the rescue. Primarily using RNAi to knockdown expression, and with the exceptions of the requirement of Bric a Brac 1 for female abdominal pigmentation and Myb oncogene-like for wing development, no evidence was found for a role of the other 16 nonresident transcription factor in the transcription factor phenotypes assessed. Therefore, these 16 rescues are likely due to functional complementation and not due to the expression of an epistatic function in the developmental/behavioral pathway. Phenotypic nonspecificity is both differentially pleiotropic and frequent, as on average 1 in 10-20 nonresident transcription factors rescue a phenotype. These observations will be important in future considerations of transcription factors function.