Codon Bias Patterns of E.coliE.coli's Interacting Proteins

Synonymous codons, i.e., DNA nucleotide triplets coding for the same amino acid, are used differently across the variety of living organisms. The biological meaning of this phenomenon, known as codon usage bias, is still controversial. In order to shed light on this point, we propose a new codon bias index, $CompAI$, that is based on the competition between cognate and near-cognate tRNAs during translation, without being tuned to the usage bias of highly expressed genes. We perform a genome-wide evaluation of codon bias for $E.coli$, comparing $CompAI$ with other widely used indices: $tAI$, $CAI$, and $Nc$. We show that $CompAI$ and $tAI$ capture similar information by being positively correlated with gene conservation, measured by ERI, and essentiality, whereas, $CAI$ and $Nc$ appear to be less sensitive to evolutionary-functional parameters. Notably, the rate of variation of $tAI$ and $CompAI$ with ERI allows to obtain sets of genes that consistently belong to specific clusters of orthologous genes (COGs). We also investigate the correlation of codon bias at the genomic level with the network features of protein-protein interactions in $E.coli$. We find that the most densely connected communities of the network share a similar level of codon bias (as measured by $CompAI$ and $tAI$). Conversely, a small difference in codon bias between two genes is, statistically, a prerequisite for the corresponding proteins to interact. Importantly, among all codon bias indices, $CompAI$ turns out to have the most coherent distribution over the communities of the interactome, pointing to the significance of competition among cognate and near-cognate tRNAs for explaining codon usage adaptation

Essentiality, conservation, evolutionary pressure and codon bias in bacterial genes

Essential genes constitute the core of genes which cannot be mutated too much nor lost along the adaptive evolutionary history of a species. Natural selection is expected to be stricter on essential genes and on conserved (highly shared) genes, than on genes that are either nonessential or peculiar to a single or a few species. In order to further assess this expectation, we study here how essentiality of a gene is connected with its degree of conservation among several unrelated bacterial species, each one characterised by its own codon usage bias. Confirming previous results on E- Coli, we show the existence of a universal exponential correlation between gene essentiality and conservation in bacteria. Moreover, we show that, within each bacterial genome, there are at least two groups of functionally distinct genes, characterised by different levels of conservation and codon bias: i) a core of essential genes, mainly related to cellular information processing; ii) a set of less conserved genes with prevalent functions related to metabolism. The genes in the first group are more retained among species, are subject to a relatively purifying conservative selection and display a more selected choice of synonymous codons.The core of essential genes is close to the minimal bacterial genome, which is in the focus of recent studies in synthetic biology, though we confirm that othologues of genes that are essential in one species are not necessarily essential in other species. We also list a set of highly shared genes, which could constitute a reservoir of targets for new anti-microbial drugs

Co-evolution between Codon Usage and Protein-Protein Interaction in Bacteria

We study the correlation between the codon usage bias of genetic sequences and the network features of protein-protein interaction (PPI) in bacterial species. We use PCA techniques in the space of codon bias indices to show that genes with similar patterns of codon usage have a significantly higher probability that their encoded proteins are functionally connected and interacting. Importantly, this signal emerges when multiple aspects of codon bias are taken into account at the same time. The present study extends our previous observations on E.Coli over a wide set of 34 bacteria. These findings could allow for future investigations on the possible effects of codon bias on the topology of the PPI network, with the aim of improving existing bioinformatics methods for predicting protein interactions

(Meta)genomic insights into the pathogenome of Cellulosimicrobium cellulans

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 6 (2016): 25527, doi:10.1038/srep25527.Despite having serious clinical manifestations, Cellulosimicrobium cellulans remain under-reported with only three genome sequences available at the time of writing. Genome sequences of C. cellulans LMG16121, C. cellulans J36 and Cellulosimicrobium sp. strain MM were used to determine distribution of pathogenicity islands (PAIs) across C. cellulans, which revealed 49 potential marker genes with known association to human infections, e.g. Fic and VbhA toxin-antitoxin system. Oligonucleotide composition-based analysis of orthologous proteins (n = 791) across three genomes revealed significant negative correlation (P < 0.05) between frequency of optimal codons (Fopt) and gene G+C content, highlighting the G+C-biased gene conversion (gBGC) effect across Cellulosimicrobium strains. Bayesian molecular-clock analysis performed on three virulent PAI proteins (Fic; D-alanyl-D-alanine-carboxypeptidase; transposase) dated the divergence event at 300 million years ago from the most common recent ancestor. Synteny-based annotation of hypothetical proteins highlighted gene transfers from non-pathogenic bacteria as a key factor in the evolution of PAIs. Additonally, deciphering the metagenomic islands using strain MM’s genome with environmental data from the site of isolation (hot-spring biofilm) revealed (an)aerobic respiration as population segregation factor across the in situ cohorts. Using reference genomes and metagenomic data, our results highlight the emergence and evolution of PAIs in the genus Cellulosimicrobium.The authors acknowledge funds from Department of Biotechnology (DBT) and National Bureau of Agriculturally Important Microorganisms (NBAIM). AS gratefully acknowledge National Bureau of Agriculturally Important Microorganisms (NBAIM) for providing research fellowship

Forbidden Synonymous Substitutions in Coding Regions

In the evolution of highly conserved genes, a few "synonymous" substitutions at third bases that would not alter the protein sequence are forbidden or very rare, presumably as a result of functional requirements of the gene or the messenger RNA. Another 10% or 20% of codons are significantly less variable by synonymous substitution than are the majority of codons. The changes that occur at the majority of third bases are subject to codon usage restrictions. These usage restrictions control sequence similarities between very distant genes. For example, 70% of third bases are identical in calmodulin genes of man and trypanosome. Third-base similarities of distant genes for conserved proteins are mathematically predicted, on the basis of the G+C composition of third bases. These observations indicate the need for reexamination of methods used to calculate synonymous substitutions

Effects of directional epistasis on molecular evolution

Forward population genetic simulations are used to explore the evolution of a sequence of nucleotide sites subject to reversible mutation under selection, mutation, and drift. Three selection schemes are studied: synergistic, antagonistic, and multiplicative interactions among sites. Their respective effects on the level of nucleotide diversity, the pattern of linkage disequilibrium, and the allele frequency spectrum are determined. Surprisingly, none of these aspects are affected by directional epistasis when the overall strength of selection is held constant (where the equilibrium allele frequencies are equal). The equilibrium mean fitness does differ with selection regime, and is relatively higher with synergistic interactions while lower with antagonistic epistasis. These findings legitimate the application of many population genetic models assuming multiplicative selection when there are actually epistatic interactions among sites, and have important implications on the evolution of recombination

Effect of exonic splicing regulation on synonymous codon usage in alternatively spliced exons of Dscam

<p>Abstract</p> <p>Background</p> <p>Synonymous codon usage is typically biased towards translationally superior codons in many organisms. In <it>Drosophila</it>, genomic data indicates that translationally optimal codons and splice optimal codons are mostly mutually exclusive, and adaptation to translational efficiency is reduced in the intron-exon boundary regions where potential exonic splicing enhancers (ESEs) reside. In contrast to genomic scale analyses on large datasets, a refined study on a well-controlled set of samples can be effective in demonstrating the effects of particular splice-related factors. <it>Down syndrome cell adhesion molecule </it>(<it>Dscam</it>) has the largest number of alternatively spliced exons (ASEs) known to date, and the splicing frequency of each ASE is accessible from the relative abundance of the transcript. Thus, these ASEs comprise a unique model system for studying the effect of splicing regulation on synonymous codon usage.</p> <p>Results</p> <p>Codon Bias Indices (CBI) in the 3' boundary regions were reduced compared to the rest of the exonic regions among 48 and 33 ASEs of exon 6 and 9 clusters, respectively. These regional differences in CBI were affected by splicing frequency and distance from adjacent exons. Synonymous divergence levels between the 3' boundary region and the remaining exonic region of exon 6 ASEs were similar. Additionally, another sensitive comparison of paralogous exonic regions in recently retrotransposed processed genes and their parental genes revealed that, in the former, the differences in CBI between what were formerly the central regions and the boundary regions gradually became smaller over time.</p> <p>Conclusion</p> <p>Analyses of the multiple ASEs of <it>Dscam </it>allowed direct tests of the effect of splice-related factors on synonymous codon usage and provided clear evidence that synonymous codon usage bias is restricted by exonic splicing signals near the intron-exon boundary. A similar synonymous divergence level between the different exonic regions suggests that the intensity of splice-related selection is generally weak and comparable to that of translational selection. Finally, the leveling off of differences in codon bias over time in retrotransposed genes meets the direct prediction of the tradeoff model that invokes conflict between translational superiority and splicing regulation, and strengthens the conclusions obtained from <it>Dscam</it>.</p