Background: The evolution of complex molecular traits such as disulphide bridges often requires multiple mutations. The intermediate steps in such evolutionary trajectories are likely to be selectively neutral or deleterious. Therefore, large populations and long times may be required to evolve such traits. Results:We propose that errors in transcription and translation may allow selection for the intermediate mutations, if the final trait provides a large enough selective advantage. We test this hypothesis using a population based model of protein evolution. Conclusion:If an individual acquires one of two mutations needed for a novel trait, the second mutation can be introduced into the phenotype due to transcription and translation errors. If the novel trait is advantageous enough, the allele with only one mutation will spread through the population, even though the gene sequence does not yet code for the complettrait. Thus, errors allow protein sequences to "look-ahead" for a more direct path to a complex trait.

Experiment showed that the response of a genotype to mutation, i.e., the magnitude of mutational change in a phenotypic property, can be correlated with the extent of phenotypic fluctuation among genetic clones. To address a possible statistical mechanical basis for such phenomena at the protein level, we consider a simple hydrophobic-polar lattice protein-chain model with an exhaustive mapping between sequence (genotype) and conformational (phenotype) spaces. Using squared end-to-end distance, R(N)(2), as an example conformational property, we study how the thermal fluctuation of a sequence's R(N)(2) may be predictive of the changes in the Boltzmann average R(N)(2) caused by single-point mutations on that sequence. We found that sequences with the same ground-state (R(N)(2))(0) exhibit a funnel-like organization under conditions favorable to chain collapse or folding: fluctuation (standard deviation sigma) of R(N)(2) tends to increase with mutational distance from a prototype sequence whose R(N)(2) deviates little from its (R(N)(2))(0). In general, large mutational decreases in R(N)(2) or in sigma are only possible for some, though not all, sequences with large sigma values. This finding suggests that single-genotype phenotypic fluctuation is a necessary, though not sufficient, indicator of evolvability toward genotypes with less phenotypic fluctuations.