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Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

All eukaryotes utilize a single termination factor, eRF1, to halt translation when the ribosome encounters one of three possible stop codons; here electron cryo-microscopy structures of ribosome–eRF1 complexes in the process of recognizing each stop codon reveal how stop codons are discriminated from sense codons. How mRNA knows when to stop Mammalian messenger RNAs utilize three stop codons, but have a single termination factor, eRF1, that can recognize all three. To understand how eRF1 can distinguish stop codons from sense codons, Alan Brown et al . determined the structures of the mammalian 80S ribosome bound to eRF1 and mRNAs containing each of the stop codons. They find that two nucleotides from the 18S rRNA are stacked with two of the stop codon nucleotides, and the next nucleotide, to compact the mRNA, a conformation that favours stop codons to the exclusion of sense codons. Termination of protein synthesis occurs when a translating ribosome encounters one of three universally conserved stop codons: UAA, UAG or UGA. Release factors recognize stop codons in the ribosomal A-site to mediate release of the nascent chain and recycling of the ribosome. Bacteria decode stop codons using two separate release factors with differing specificities for the second and third bases 1 . By contrast, eukaryotes rely on an evolutionarily unrelated omnipotent release factor (eRF1) to recognize all three stop codons 2 . The molecular basis of eRF1 discrimination for stop codons over sense codons is not known. Here we present cryo-electron microscopy (cryo-EM) structures at 3.5–3.8 Å resolution of mammalian ribosomal complexes containing eRF1 interacting with each of the three stop codons in the A-site. Binding of eRF1 flips nucleotide A1825 of 18S ribosomal RNA so that it stacks on the second and third stop codon bases. This configuration pulls the fourth position base into the A-site, where it is stabilized by stacking against G626 of 18S rRNA. Thus, eRF1 exploits two rRNA nucleotides also used during transfer RNA selection to drive messenger RNA compaction. In this compacted mRNA conformation, stop codons are favoured by a hydrogen-bonding network formed between rRNA and essential eRF1 residues that constrains the identity of the bases. These results provide a molecular framework for eukaryotic stop codon recognition and have implications for future studies on the mechanisms of canonical and premature translation termination 3 , 4 .

Abstract Codon usage bias (CUB), where certain codons are used more frequently than expected by chance, is a ubiquitous phenomenon and occurs across the tree of life. The dominant paradigm is that the proportion of preferred codons is set by weak selection. While experimental changes in codon usage have at times shown large phenotypic effects in contrast to this paradigm, genome-wide population genetic estimates have supported the weak selection model. Here we use deep genomic population sequencing of two Drosophila melanogaster populations to measure selection on synonymous sites in a way that allowed us to estimate the prevalence of both weak and strong purifying selection. We find that selection in favor of preferred codons ranges from weak (|Nes| ∼ 1) to strong (|Nes| > 10), with strong selection acting on 10–20% of synonymous sites in preferred codons. While previous studies indicated that selection at synonymous sites could be strong, this is the first study to detect and quantify strong selection specifically at the level of CUB. Further, we find that CUB-associated polymorphism accounts for the majority of strong selection on synonymous sites, with secondary contributions of splicing (selection on alternatively spliced genes, splice junctions, and spliceosome-bound sites) and transcription factor binding. Our findings support a new model of CUB and indicate that the functional importance of CUB, as well as synonymous sites in general, have been underestimated.

In each genome, synonymous codons are used with different frequencies; this general phenomenon is known as codon usage bias. It has been previously recognised that codon usage bias could affect the cellular fitness and might be associated with the ecology of microbial organisms. In this exploratory study, we investigated the relationship between codon usage bias, lifestyles (thermophiles vs. mesophiles; pathogenic vs. non-pathogenic; halophilic vs. non-halophilic; aerobic vs. anaerobic and facultative) and habitats (aquatic, terrestrial, host-associated, specialised, multiple) of 615 microbial organisms (544 bacteria and 71 archaea). Principal component analysis revealed that species with given phenotypic traits and living in similar environmental conditions have similar codon preferences, as represented by the relative synonymous codon usage (RSCU) index, and similar spectra of tRNA availability, as gauged by the tRNA gene copy number (tGCN). Moreover, by measuring the average tRNA adaptation index (tAI) for each genome, an index that can be associated with translational efficiency, we observed that organisms able to live in multiple habitats, including facultative organisms, mesophiles and pathogenic bacteria, are characterised by a reduced translational efficiency, consistently with their need to adapt to different environments. Our results show that synonymous codon choices might be under strong translational selection, which modulates the choice of the codons to differently match tRNA availability, depending on the organism’s lifestyle needs. To our knowledge, this is the first large-scale study that examines the role of codon bias and translational efficiency in the adaptation of microbial organisms to the environment in which they live.

Key Points Sexual dimorphism in gene expression is widespread across organisms and genomes. Genes with sex-biased expression, especially those with male-biased expression, tend to evolve rapidly in both protein sequence and expression level. Sex-biased genes are non-randomly distributed in the genome, with examples of both under-representation and over-representation on the X chromosome. There is mounting evidence that positive selection is the driving force behind the rapid evolution of sex-biased genes. This is probably caused by sexual selection and antagonistic coevolution between the sexes. Sex-linked genes that escape dosage compensation constitute a special case of sex-biased gene expression. There are several scenarios for the origin of sex-biased genes, including single-locus antagonism, sexual antagonism plus gene duplication and duplication of sex-biased genes. Most of the differences between males and females are due to differences in expression levels of certain genes. These genes have several interesting properties, such as rapid sequence evolution and an odd distribution across the genome. Differences between males and females in the optimal phenotype that is favoured by selection can be resolved by the evolution of differential gene expression in the two sexes. Microarray experiments have shown that such sex-biased gene expression is widespread across organisms and genomes. Sex-biased genes show unusually rapid sequence evolution, are often labile in their pattern of expression, and are non-randomly distributed in the genome. Here we discuss the characteristics and expression of sex-biased genes, and the selective forces that shape this previously unappreciated source of phenotypic diversity. Sex-biased gene expression has implications beyond just evolutionary biology, including for medical genetics.

tRNA modifications are crucial for efficient protein synthesis, impacting codon recognition, tRNA stability, and translation rates. RNA viruses hijack the host’s translational machinery, including the pool of modified tRNA, to translate their own genomes. However, the mismatch between viral and host codon usage can lead to a limited availability of specific tRNA leading to ribosome stalling, posing a significant challenge for efficient protein translation. While some viruses address this challenge through codon optimization, we show here that SARS-CoV-2 (Coronavirus) and the Zika virus (ZIKV; Flavivirus) adopt a different approach, manipulating the host tRNA epitranscriptome. Analysis of codon bias indices confirmed a substantial divergence between viral and host codon usage, revealing a strong preference in viral genes for codons decoded by tRNAs requiring U34 wobble modification. Monitoring tRNA modification dynamics in infected cells showed that both SARS-CoV2 and ZIKV enhance U34 tRNA modifications during infection. Strikingly, impairing U34 tRNAs profoundly impacted viral replication, underscoring the strict reliance of SARS-CoV-2 and ZIKV on manipulating the host tRNA epitranscriptome to support the efficient translation of their genome.

The central dogma of molecular biology entails that genetic information is transferred from nucleic acid to proteins. Notwithstanding retro-transcribing genetic elements, DNA is transcribed to RNA which in turn is translated into proteins. Recent advancements have shown that each stage is regulated to control protein abundances for a variety of essential physiological processes. In this regard, mRNA regulation is essential in fine-tuning or calibrating protein abundances. In this review, we would like to discuss one of several mRNA-intrinsic features of mRNA regulation that has been gaining traction of recent—codon bias and optimality. Specifically, we address the effects of codon bias with regard to codon optimality in several biological processes centred on translation, such as mRNA stability and protein folding among others. Finally, we examine how different organisms or cell types, through this system, are able to coordinate physiological pathways to respond to a variety of stress or growth conditions.

Background The genus Caragana , known for its adaptability and high forage value, is commonly planted to rehabilitate barren land and prevent desertification. Several Caragana species are also used for medicinal purposes. Analysis of synonymous codon usage bias and their primary influencing factors in chloroplast genomes aims to provide insights into molecular research and germplasm innovation for Caragana plants. Results The GC content of the five Caragana species ranged from 36.00% to 37.10%, showing a preference for codons ending in A/U, although the codon bias was weak. The screening identified nine to twelve optimal codons, but their frequency of use was low. Correlation analysis, neutrality plots, ENC plots and PR2 plots of the parameters identified two potential groups among the five species: Caragana arborescens and Caragana jubata , and Caragana turkestanica , Caragana opulens and Caragana tibetica . These groups showed a high level of intragroup similarity in the parameter analyses. In the RSCU cluster tree analysis, Caragana turkestanica and Caragana arborescens grouped together, while Caragana tibetica , Caragana jubata and Caragana opulens formed a separate clade in the CDS sequence and complete sequence phylogenetic tree analysis. Conclusions The codon usage bias in the chloroplast genomes of the five Caragana species showed high similarity, suggesting that natural selection has a greater influence on codon bias than mutation. Furthermore, the identified optimal codons provide valuable insights for germplasm improvement of Caragana plants.

Nonsense codons taken as read The three 'nonsense' or 'stop' codons that signal the ribosome to cease translation — UAA, UAG and UGA — all contain an initial uridine residue. John Karijolich and Yi-Tao Yu demonstrate that isomerization of this uridine, converting it to pseudouridine (Ψ), allows the codons to be read by the ribosome in vivo . Specific amino acids are inserted into the resulting protein, with ΨAA and ΨAG coding for serine and threonine, and ΨGA for tyrosine and phenylalanine. Although there is yet no evidence for a physiological role for this RNA modification, it could offer a way of expanding the genetic code. Similar RNA modification could also be useful as a means of nonsense suppression in vivo , either experimentally or clinically. All three translation termination codons, or nonsense codons, contain a uridine residue at the first position of the codon 1 , 2 , 3 . Here, we demonstrate that pseudouridylation (conversion of uridine into pseudouridine (Ψ), ref. 4 ) of nonsense codons suppresses translation termination both in vitro and in vivo . In vivo targeting of nonsense codons is accomplished by the expression of an H/ACA RNA capable of directing the isomerization of uridine to Ψ within the nonsense codon. Thus, targeted pseudouridylation represents a novel approach for promoting nonsense suppression in vivo . Remarkably, we also show that pseudouridylated nonsense codons code for amino acids with similar properties. Specifically, ΨAA and ΨAG code for serine and threonine, whereas ΨGA codes for tyrosine and phenylalanine, thus suggesting a new mode of decoding. Our results also suggest that RNA modification, as a naturally occurring mechanism, may offer a new way to expand the genetic code.

The present study was carried out on 62 genome sequences of members of the family Anelloviridae, as there have been no reports of genome analysis of these DNA viruses using a bioinformatics approach. The genes were found to be rich in AC content with low codon usage bias (CUB). Relative synonymous codon usage (RSCU) values identified the preferred codons for each amino acid in the family. The codon AGA was overrepresented, while the codons TCG, TTG, CGG, CGT, ACG, GCG and GAT were underrepresented in all of the genomes. A significant correlation was found between the effective number of codons (ENC) and base constraints, indicating that compositional properties might have influenced the CUB. A highly significant correlation was observed between the overall base content and the base content at the third codon position, indicating that mutations might have affected the CUB. A highly significant positive correlation was observed between GC12 and GC3 (r = 0.904, p < 0.01), which indicated that directional mutation pressure influenced all three codon positions. A neutrality plot revealed that the contribution of mutation and natural selection in determining the CUB was 58.6% and 41.4%, respectively.