Extent and Effects of Selection to Reduce Synthetic Cost of Highly Expressed Proteins

Organisms that preferentially utilize less biosynthetically expensive amino acids in highly expressed genes exhibit metabolic efficiency. Exploration of this phenomenon has been limited to six prokaryotes. I present a large scale analysis of metabolic efficiency in prokaryotic organisms and analysis of two eukaryotes (Saccharomyces cerevisiae and humans). Examination of 73 bacteria reveals the presence of metabolic efficiency in 66 organisms. The average correlation between amino acid biosynthetic cost and CAI scores in these organisms is -0.21. The seven organisms that did not exhibit metabolic efficiency are all Lactobacilli and highly auxotrophic. Saccharomyces cerevisiae exhibits significant trends between average amino acid biosynthetic cost and CAI both when aerobic and anaerobic costs are considered. The treatment of amino acids in the seven organisms and the dual amino acid costs of Saccharomyces cerevisiae led to the examination of perceived cost of amino acid acquisition. Linear regression was utilized to calculate amino acid perceived cost in 11 organisms auxotrophic for a single amino acid and 13 prototrophic for all amino acids. The resulting costs for the auxotrophic amino acids are, in general, highly negative implying that auxotrophic organisms receive an energy dividend for utilizing amino acids they cannot produce. The results make it unlikely that linear regression is a suitable method for determining perceived cost. In order to determine the effect of metabolic efficiency I examined the cost of conserved versus non-conserved positions within homologous proteins. Positions that were variable in human, mouse, dog and cow utilized less expensive amino acids while conserved positions utilized more expensive amino acids. These results indicate that natural selection generally results in proteins with lower average amino acid biosynthetic costs. Human genes with CpG islands have been shown to be highly expressed in all tissues. Comparing the cost of these genes with genes not associated with CpG islands shows a lower average cost for the highly expressed genes demonstrating that metabolic efficiency is a significant evolutionary force in humans. Metabolic efficiency appears to drive amino acid substitutions in both simple one celled organisms and complex multicellular organisms and is most strongly manifested in variable regions of a protein