When does codon choice matter in translation?

Synonymous mutations, which change a gene sequence but not the protein it encodes, are considered “silent.” Yet some synonymous mutations hobble proteins by perturbing how well the protein is translated and folded, affecting function. One such synonymous mutation in the cystic fibrosis gene, CFTR, exacerbates the disease. To learn the contextual rules that define when synonymous mutations matter, we are surveying every synonymous mutation of a yeast CFTR analog, YOR1. By measuring each mutation’s effect on protein output and yeast growth, we can build a model for better design of synthetic mRNAs to advance their use in medicine and technology.