Resolving the Molecular Mechanisms by Which DNA Mutations Alter the Function of a Genetic Switch

Each human genome possesses around a million mutations that are genetic baggage from DNA replication mistakes or “mutations” that occurred in the past. Each mutation can have one of three outcomes on an individual, these are to improve, reduce, or have no effect on health. Moreover, the effects of such mutations can depend on the presence or absence of other mutations, so called epistatic interactions. A major goal of genomic medicine is to glean diagnostic or predictive health information from the genome sequences of individuals. However, this goal remains out of reach as the effects of mutations and epistatic interactions are difficult to predict without knowing the function of the DNA sequence they reside in. This difficulty is especially heightened for mutations occurring in cis-regulatory element sequences that act as switches to control gene transcription. The research I plan to perform for my Honors Thesis is to use a fruit fly model to test hypotheses about the molecular mechanisms by which mutations alter a genetic switch’s activity and whether these mutations are subjected to the tyranny of epistatic interactions. I will study the Drosophila melanogaster dimorphic element which is a transcription-regulating switch for the bric-à-brac genes. Three mutations in the dimorphic element were identified that individually alter the level of bric-à-brac transcription. The presence or absence of epistatic interactions will be determined by measuring the activity of dimorphic elements from related species that have been engineered to possess the Drosophila melanogaster mutations. I will also test the hypothesis that these mutations impart their effects by creating or destroying binding sites for proteins known as transcription factors. The results will provide a sorely needed example where an understanding of molecular mechanisms bridges the gap between a DNA sequence and its in vivo function