Sammet et al. BMC Evolutionary Biology 2010, 10:178 http://www.biomedcentral.com/1471-2148/10/178 Open Access RESEARCH ARTICLE © 2010 Sammet et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Research article Comparison of translation loads for standard and alternative genetic codes Stefanie Gabriele Sammet 1,3 , Ugo Bastolla* 2 and Markus Porto* 1,4 Abstract Background: The (almost) universality of the genetic code is one of the most intriguing properties of cellular life. Nevertheless, several variants of the standard genetic code have been observed, which differ in one or several of 64 codon assignments and occur mainly in mitochondrial genomes and in nuclear genomes of some bacterial and eukaryotic parasites. These variants are usually considered to be the result of non-adaptive evolution. It has been shown that the standard genetic code is preferential to randomly assembled codes for its ability to reduce the effects of errors in protein translation. Results: Using a genotype-to-phenotype mapping based on a quantitative model of protein folding, we compare the standard genetic code to seven of its naturally occurring variants with respect to the fitness loss associated to mistranslation and mutation. These fitness losses are computed through computer simulations of protein evolution with mutations that are either neutral or lethal, and different mutation biases, which influence the balance between unfolding and misfolding stability. We show that the alternative codes may produce significantly different mutation and translation loads, particularly for genomes evolving with a rather large mutation bias. Most of the alternative genetic codes are found to be disadvantageous to the standard code, in agreement with the view that the change of genetic code is a mutationally driven event. Nevertheless, one of the studied alternative genetic codes is predicted to be preferable to the standard code for a broad range of mutation biases. Conclusions: Our results show that, with one exception, the standard genetic code is generally better able to reduce the translation load than the naturally occurring variants studied here. Besides this exception, some of the other alternative genetic codes are predicted to be better adapted for extreme mutation biases. Hence, the fixation of alternative genetic codes might be a neutral or nearly-neutral event in the majority of the cases, but adaptation cannot be excluded for some of the studied cases. Background The origin and universality of the genetic code is one of the biggest enigmas in biology [1]. Soon after the genetic code of Escherichia coli was deciphered [2], it was real- ized that this specific code out of more than 10 84 possible codes is shared by all studied life forms (albeit sometimes with minor modifications). The question of how this spe- cific code appeared and which physical or chemical con- straints and evolutionary forces have shaped its highly non-random codon assignment is subject of an intense debate. In particular, the feature that codons differing by a single nucleotide usually code for either the same or a chemically very similar amino acid and the associated block structure of the assignments is thought to be a nec- essary condition for the robustness of the genetic code both against mutations as well as against errors in trans- lation [3-13]. This robustness reduces fitness losses due to mutation and mistranslation, which is believed to be a major force in coding sequence evolution [14]. There are three basic theories of the genetic code's nature, origin, and evolution. Whereas the stereochemical theory first proposed by Gamow [15] asserts that the codon assign- ment was originated by the physicochemical affinity between the amino acid and the codon or anticodon, the adaptive theory posits that the genetic code was shaped under selection for robustness, either against mutations [16,17] or against translation errors [18,19], or against * Correspondence: ubastolla@cbm.uam.es, porto@thp.uni-koeln.de 1 Institut für Festkörperphysik, Technische Universität Darmstadt, Hochschulstr. 8, 64289 Darmstadt, Germany 2 Centro de Biología Molecular 'Severo Ochoa', (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain Full list of author information is available at the end of the article