Cellular efficiency in protein translation is an important fitness determinant in rapidly growing organisms. It is widely believed that synonymous codons are translated with unequal speeds and that translational efficiency is maximized by the exclusive use of rapidly translated codons. Here we estimate the in vivo translational speeds of all sense codons from the budding yeast Saccharomyces cerevisiae . Surprisingly, preferentially used codons are not translated faster than unpreferred ones. We hypothesize that this phenomenon is a result of codon usage in proportion to cognate tRNA concentrations, the optimal strategy in enhancing translational efficiency under tRNA shortage. Our predicted codon–tRNA balance is indeed observed from all model eukaryotes examined, and its impact on translational efficiency is further validated experimentally. Our study reveals a previously unsuspected mechanism by which unequal codon usage increases translational efficiency, demonstrates widespread natural selection for translational efficiency, and offers new strategies to improve synthetic biology.

SUMMARY Antagonistic pleiotropy (AP) or genetic tradeoff is an important concept invoked frequently in theories of aging, cancer, genetic disease, and other common phenomena. But, it is unclear how prevalent AP is, which genes are subject to AP, and to what extent and how AP may be resolved. By measuring the fitness difference between the wild-type and null alleles of ~5000 nonessential genes in yeast, we find that, in any given environment, yeast expresses hundreds of genes that harm rather than benefit the organism, demonstrating widespread AP. Nonetheless, under sufficient selection, AP is often resolvable through regulatory evolution, primarily by trans-acting changes, although in one case we also detect a cis-acting change and localize its causal mutation. AP resolution, however, is slower in smaller populations, predicting more unresolved AP in multicellular organisms than in yeast. These findings provide the empirical foundation for AP-dependent theories and have broad biomedical and evolutionary implications.

Although evolutionary theories predict functional divergence between duplicate genes, many old duplicates still maintain a high degree of functional similarity and are synthetically lethal or sick, an observation that has puzzled many geneticists. We propose that expression reduction, a special type of subfunctionalization, facilitates the retention of duplicates and the conservation of their ancestral functions. Consistent with this hypothesis, gene expression data from both yeasts and mammals show a substantial decrease in the amount of gene expression after duplication. While the majority of the expression reductions are likely to be neutral, some are apparently beneficial to rebalancing gene dosage after duplication. Gene duplication without functional divergenceGene duplication is prevalent in all three domains of life and is the major source of new genes [1][2]. Immediately after gene duplication, the two daughter genes are usually functionally redundant, especially when the entire gene together with its regulatory region is duplicated. Thus, mutations that knock out one of the duplicates are invisible to natural selection. Consequently, usually only one daughter gene is stably retained in the genome while the other degenerates into a pseudogene that is eventually lost. Therefore, with the exception of a small number of genes for which an increased dosage is beneficial (e.g., ribosomal RNA and histone genes) [2], the two daughter genes cannot be stably maintained in the same genome unless they escape from the usual fate of pseudogenization by quickly diverging in function, which may occur by the acquisition of new functions (neofunctionalization) [1], subdivision of ancestral functions (subfunctionalization) [3], or a combination of the two [4]. Surprisingly, however, several studies in yeast and nematode have found many duplicate gene pairs with negative epistasis [5][6][7][8][9], meaning that deleting both gene copies produces a significantly larger defect than expected from the effects of individual deletions. Negative epistasis is caused by functional redundancy [10]. While one might think that most of these negatively epistatic gene pairs are young duplicates that have not had sufficient time to diverge in function, this is not Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [7][8][9]. In fact, many of them are quite old [7][8][9] and some originated as early as a billion years ago [7]. The long-term maintenance of functional redundancy of duplicate genes is unexpected and puzzling. NIH Public Access Reduced expression can lead to the maintenance of fu...

The rapid accumulation of mutations in the SARS-CoV-2 Omicron variant that enabled its outbreak raises questions as to whether its proximal origin occurred in humans or another mammalian host. Here, we identified 45 point mutations that Omicron acquired since divergence from the B.1.1 lineage. We found that the Omicron spike protein sequence was subjected to stronger positive selection than that of any reported SARS-CoV-2 variants known to evolve persistently in human hosts, suggesting a possibility of host-jumping. The molecular spectrum of mutations ( i.e. , the relative frequency of the 12 types of base substitutions) acquired by the progenitor of Omicron was significantly different from the spectrum for viruses that evolved in human patients, but resembled the spectra associated with virus evolution in a mouse cellular environment. Furthermore, mutations in the Omicron spike protein significantly overlapped with SARS-CoV-2 mutations known to promote adaptation to mouse hosts, particularly through enhanced spike protein binding affinity for the mouse cell entry receptor. Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.