RARELY USED CODONS in organ development
We have extended our interest in "extreme genome variation" in developmental biology to understand how distinct cell types and molecules differentially respond to biased use of synonymous codons. We identified Drosophila tissues that resist such codon usage bias and are exploring how this resistance enables specific tissues to translate a unique and tissue-specific set of proteins. Specifically, we developed codon-altered GFP reporters to conduct an animal-wide screen for tissue-specific impacts of rare codons. This screen revealed that two tissues, the testis and brain, are unique in the ability to robustly produce protein from rare codon-enriched transcripts. We have extended these findings to endogenously expressed genes in the testis of both flies and humans, revealing that differential sensitivities to codon usage bias enables tissue-specific expression. Further, in collaboration with Chris Counter's lab (Duke), we established a model to study the codon-dependent regulation of the Ras signaling pathway. In a genome-wide screen, we identified the first ever Ras regulators that are dependent on a low-intensity state of the Ras/MAPK pathway and showed that mutants lacking these regulators are able to achieve a heightened (oncogenic) signaling state.