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Allelic drive: a strategy to correct disease-causing mutations modeled in Drosophila melanogaster


Allelic drive is a new gene drive technology that allows for the selective cleavage of detrimental alleles at a locus that is separate from the inserted genetic element. This new technology has the potential to drive intact desired alleles in populations, however it is unknown if this strategy can also be used to fix mutations in somatic tissues to restore partial or complete function of mutant alleles. We have defined and created a combination of mutant alleles in the Notch gene of Drosophila Melanogaster amenable to repair using allelic replacement: a Cas9-based strategy, in which selective cleavage of a mutant allele is followed by repair using the wild-type homologous chromosome. In addition, we have identified other phenotypes (shorter lifespan and intestinal stem cell phenotypes) in mutant Drosophila that may be alleviated by a restoration

of gene function. Additionally, we have been able to create a line of Drosophila expressing a guide RNA that can be used in allelic drive to selectively remove a mutated allele. Finally, background experiments have been conducted and data collected in preparation for experiments aimed to measure reduction of known mutant phenotypes in the presence of an allele-specific guide RNA and a Cas9 nuclease. If allelic drive is shown to be successful in restoring Notch gene function, these concepts have the potential to be transferred to more complex animals and even be used to treat human genetic disorders.

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