Strategies for efficiency and accuracy in gene expression

Recently there has been a shift in the perception of problems associated with the mechanisms of gene expression. Formerly it seemed that the problem was to discover where the remarkable accuracy of gene expression originated. The mystery was that all model system studies suggested that the binding interactions of nucleotides are not sufficiently stereo-specific to support the accuracy of either transcription or of translation. The introduction of the Hopfield-Ninio model of substrate proofreading demystified this aspect of the accuracy of gene expression, but it generated another set of problems. Thus, the way to get high accuracy out a low fidelity elementary process such as base pairing is to repeat the elementary step a sufficient number of times. Since there is no principle limit on the number of allowable repetitions, there is no principle limit on the attainable accuracy. What then sets the error rates of gene expression? This series of three articles will address this question. In this first article, the notion of a maximized kinetic efficiency for the translation apparatus will be introduced. A simple optimization principle will then be used as a tool to explore the consequences of using different coding strategies to specify the sequences of proteins that are expressed selectively under different growth conditions. In the second article the antagonistic relationship between kinetic efficiency and accuracy of translation will be explored. The notion of a kinetic optimization of the costs of errors and the costs of accuracy will be introduced and used to explain the growth phenotypes of mutants with altered translational accuracy. The costs associated with errors of translocation will be contrasted with those associated with missense errors in the third article. In addition, I will introduce the notion that there is a physical constraint in translation that imposes a reciprocal relationship between the accuracy of aminoacyl-tRNA selection and the accuracy of messenger RNA movement. This reciprocal relationship will provide some insight into the nature of drug dependence in bacteria and will also suggest the outlines of an answer to our original question. In particular, I will suggest that the lower level of the missense error rate is determined, at least in part, by the upper level of mRNA translocation errors that is tolerable. Likewise, the accuracy of translocation may be constrained by the kinetic costs associated with excessive accuracy of tRNA selection.