Significant Impact of Protein Dispensability on the Instantaneous Rate of Protein Evolution

Abstract

The neutral theory of molecular evolution predicts that important proteins evolve more slowly than unimportant ones. High-throughput gene-knockout experiments in model organisms have provided information on the dispensability, and therefore importance, of thousands of proteins in a genome. However, previous studies of the correlation between protein dispensability and evolutionary rate were equivocal, and it has been proposed that the observed correlation is due to the covariation with the level of gene expression or is limited to duplicate genes. We here analyzed the gene dispensability data of the yeast Saccharomyces cerevisiae and estimated protein evolutionary rates by comparing S. cerevisiae with nine species of varying degrees of divergence from S. cerevisiae. The correlation between gene dispensability and evolutionary rate, although low, is highly significant, even when the gene expression level is controlled for or when duplicate genes are excluded. Our results thus support the hypothesis of lower evolution rates for more important proteins, a widely used principle in the daily practice of molecular biology. When the evolutionary rate is estimated from closely related species, the ratio between the mean rate of nonessential proteins to that of essential proteins is 1.4. This ratio declines to 1.1 when the evolutionary rate is estimated from distantly related species, suggesting that the importance of a protein may change in evolution, so the dispensability data obtained from a model organism only predicts a short-term rate of protein evolution. A comparison of the fitness contributions of orthologous genes in yeast and nematode supports this conclusion.

Integration of New Genes into Cellular Networks, and Their Structural Maturation

“…The difference between proto-genes and ancient genes is still highly significant (P ,, 0.001, ANCOVA), indicating that it is not merely a by-product of compositional differences between ancient and proto-genes (see Figure 4). evolutionary rate (Zhang and He 2005). The analysis of gene loss in this study indicates that proto-gene turnover exists; young genes with lower conservation levels (4-5) are lost considerably more easily in S. paradoxus and S. mikatae than ancient genes ( Figure 5), which are more integrated into cellular networks.…”

Genomic evidence for elevated mutation rates in highly expressed genes

“…Our finding of elevated mutation rates in highly expressed genes in yeast and human germline has several important implications. First, because highly expressed genes tend to have more important roles than lowly expressed genes [45] and because most mutations are deleterious, our finding suggests that (i) spontaneous mutations are more harmful than is now appreciated on the basis of the assumption of homogenous mutation rates and that (ii) the actual mutation load is likely greater than the present estimate. Second, the fact that transcription is overall a mutagen implies the possibility of natural selection for reduced transcription from an unnecessarily high level due simply to the benefit of reducing deleterious mutations.…”

Nascent RNA folding mitigates transcription-associated mutagenesis

“…This correlation could have resulted from differential natural selection for minimized mutational load, because highly expressed genes are functionally more important (Zhang and He 2005) and subject to severer TAM (Park et al 2012) than lowly expressed genes. Nonetheless, selection for reduced mutational load is extremely weak , and our calculation indicates that the selective advantage of a singlenucleotide change that reduces the mutation rate at a few sites by enhancing local nascent RNA folding is one to several orders of magnitude smaller than what natural selection can detect in yeast and human (see Methods).…”