Specific Codons Control Cellular Resources and Fitness

Abstract There is a degeneracy in codons – but they are not equivalent. While there is an understanding that codon use is unequal in native genes, there is less knowledge of how this usage bias modulates the supply and demand of protein translation resources. Here we investigate how the partitioning of microbial translational resources, specifically through allocation of tRNA by incorporating dissimilar codon usage bias, can drastically alter expression of proteins and reduce the burden on the host resources. By isolating individual codons experimentally, we find heterologous gene expression can trans-regulate fitness of the host and other heterologous genes. Interestingly, specific codons drive profitable or catastrophic phenotypic outcomes. We correlate codon usage patterns with genetic fitness and empirically derive a novel coding scheme for multi-gene expression called Codon Harmony Index (CHI, χ). CHI enables the design of harmonious multi-gene expression systems while avoiding catastrophic cellular burden.