The understanding of selective constraints affecting genes is a major issue in biology. It is well established that gene expression level is a major determinant of the rate of protein evolution, but the reasons for this relationship remain highly debated. Here we demonstrate that gene expression is also a major determinant of the evolution of gene dosage: the rate of gene losses after whole genome duplications in the Paramecium lineage is negatively correlated to the level of gene expression, and this relationship is not a byproduct of other factors known to affect the fate of gene duplicates. This indicates that changes in gene dosage are generally more deleterious for highly expressed genes. This rule also holds for other taxa: in yeast, we find a clear relationship between gene expression level and the fitness impact of reduction in gene dosage. To explain these observations, we propose a model based on the fact that the optimal expression level of a gene corresponds to a trade-off between the benefit and cost of its expression. This COSTEX model predicts that selective pressure against mutations changing gene expression level or affecting the encoded protein should on average be stronger in highly expressed genes and hence that both the frequency of gene loss and the rate of protein evolution should correlate negatively with gene expression. Thus, the COSTEX model provides a simple and common explanation for the general relationship observed between the level of gene expression and the different facets of gene evolution. Author Summary The analysis of gene evolution is a powerful approach to recognize the genetic features that contribute to the fitness of organisms. It was shown previously that selective constraints on protein sequences increase with expression level. This observation was surprising because there is a priori no reason why lowly expressed genes should be less important than highly expressed genes for the proper function of an organism. Here we show that selective pressure on the evolution of gene dosage, which is another important aspect of gene evolution, is also directly dependent on gene expression level. To explain these observations, we propose a model based on the fact that gene expression is a costly process (notably protein synthesis), so that there is an optimal expression level for each gene corresponding to a trade-off between the benefit and the cost of its expression. This model predicts that selective pressure on gene expression level or on the encoded protein should on average be stronger in highly expressed genes, providing a simple and common explanation for the general relationship observed between gene expression and the different facets of gene evolution.
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