Neutral evolution of Protein-protein interactions: a computational study using simple models

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions are central to cellular organization, and must have appeared at an early stage of evolution. To understand better their role, we consider a simple model of protein evolution and determine the effect of an explicit selection for Protein-protein interactions.</p> <p>Results</p> <p>In the model, viable sequences all have the same fitness, following the neutral evolution theory. A very simple, two-dimensional lattice representation of the protein structures is used, and the model only considers two kinds of amino acids: hydrophobic and polar. With these approximations, exact calculations are performed. The results do not depend too strongly on these assumptions, since a model using a 3D, off-lattice representation of the proteins gives results in qualitative agreement with the 2D one. With both models, the evolutionary dynamics lead to a steady state population that is enriched in sequences that dimerize with a high affinity, well beyond the minimal level needed to survive. Correspondingly, sequences close to the viability threshold are less abundant in the steady state, being subject to a larger proportion of lethal mutations. The set of viable sequences has a "funnel" shape, consistent with earlier studies: sequences that are highly populated in the steady state are "close" to each other (with proximity being measured by the number of amino acids that differ).</p> <p>Conclusion</p> <p>This bias in the the steady state sequences should lead to an increased resistance of the population to environmental change and an increased ability to evolve.</p

Neutral evolution of proteins: The superfunnel in sequence space and its relation to mutational robustness.

International audienceFollowing Kimura's neutral theory of molecular evolution [M. Kimura, The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983) (reprinted in 1986)], it has become common to assume that the vast majority of viable mutations of a gene confer little or no functional advantage. Yet, in silico models of protein evolution have shown that mutational robustness of sequences could be selected for, even in the context of neutral evolution. The evolution of a biological population can be seen as a diffusion on the network of viable sequences. This network is called a "neutral network." Depending on the mutation rate mu and the population size N, the biological population can evolve purely randomly (muN1). The stringency of the selection depends not only on the product muN but also on the exact topology of the neutral network, the special arrangement of which was named "superfunnel." Even though the relation between mutation rate, population size, and selection was thoroughly investigated, a study of the salient topological features of the superfunnel that could affect the strength of the selection was wanting. This question is addressed in this study. We use two different models of proteins: on lattice and off lattice. We compare neutral networks computed using these models to random networks. From this, we identify two important factors of the topology that determine the stringency of the selection for mutationally robust sequences. First, the presence of highly connected nodes ("hubs") in the network increases the selection for mutationally robust sequences. Second, the stringency of the selection increases when the correlation between a sequence's mutational robustness and its neighbors' increases. The latter finding relates a global characteristic of the neutral network to a local one, which is attainable through experiments or molecular modeling

Residual subsidence analysis after the end of coalmine work. Example from Lorraine colliery, France

International audienceThis paper describes the residual movements associated with the deep coalmines. The studied case relates to works located into Lorraine coal basin. The paper is divided into two sections. The first one describes subsidence phenomena, especially the residual phase in terms of amplitude, duration and localization. The second one focus on Morsbach case: the total and residual subsidence measurements will be analyzed and compared to the state of the art as well as the currant knowledge. The results of the analysis show that the duration of residual movements does not exceed 24 months and their amplitude is about 5 % of total subsidence. We analyze also the declarations of the mining damage during and after the mining period. Damages occur, after this period are probably due to late observations.Cet article décrit les mouvements résiduels associés à l'exploitation des mines de charbon à grande profondeur. Le cas traité concerne le secteur de Morsbach, influencé par une exploitation de charbon en Lorraine. L'article se décompose en deux parties : la première partie décrit le phénomène d'affaissement, et particulièrement la phase résiduelle de l'affaissement (amplitude, durée, localisation), la deuxième partie est consacrée au cas de Morsbach, pour lequel nous analyserons les mesures d'affaissement (totales et résiduelles) par rapport à l'état de la connaissance. Les résultats de l'analyse montrent que la durée de l'affaissement résiduel ne dépasse pas 24 mois et que son amplitude est de l'ordre de 5 % de l'affaissement total. Nous avons également analysé les déclarations des dommages et des dégâts miniers pendant et après l'exploitation. Les dommages observés après l'arrêt des travaux sont probablement dus à des observations tardives

A systems biology approach to investigate the response of Synechocystis sp. PCC6803 to a high salt environment.

BACKGROUND: Salt overloading during agricultural processes is causing a decrease in crop productivity due to saline sensitivity. Salt tolerant cyanobacteria share many cellular characteristics with higher plants and therefore make ideal model systems for studying salinity stress. Here, the response of fully adapted Synechocystis sp. PCC6803 cells to the addition of 6% w/v NaCl was investigated using proteomics combined with targeted analysis of transcripts. RESULTS: Isobaric mass tagging of peptides led to accurate relative quantitation and identification of 378 proteins, and approximately 40% of these were differentially expressed after incubation in BG-11 media supplemented with 6% salt for 9 days. Protein abundance changes were related to essential cellular functional alterations. Differentially expressed proteins involved in metabolic responses were also analysed using the probabilitistic tool Mixed Model on Graphs (MMG), where the role of energy conversion through glycolysis and reducing power through pentose phosphate pathway were highlighted. Temporal RT-qPCR experiments were also run to investigate protein expression changes at the transcript level, for 14 non-metabolic proteins. In 9 out of 14 cases the mRNA changes were in accordance with the proteins. CONCLUSION: Synechocystis sp. PCC6803 has the ability to regulate essential metabolic processes to enable survival in high salt environments. This adaptation strategy is assisted by further regulation of proteins involved in non-metabolic cellular processes, supported by transcriptional and post-transcriptional control. This study demonstrates the effectiveness of using a systems biology approach in answering environmental, and in particular, salt adaptation questions in Synechocystis sp. PCC6803

Multi-omic modeling of translational efficiency for synthetic gene design

Controlled expression of recombinant genes in CHO cells for advanced cell engineering will require precise, coordinated control of the synthetic processes that underpin the production of specific recombinant products or the optimal stoichiometry of functional effector proteins for multigene engineering applications. Although control of recombinant gene transcription in CHO host cells is now possible, technologies that enable control of recombinant mRNA translation rate are lacking. This is undesirable as in eukaryotic cells, cellular mRNA concentration itself may only explain a relatively small proportion of the variation in cellular protein abundance; mRNA translation rate is by far the most important contributor to cellular protein concentration. We have taken a top-down, genome-scale computational modeling approach to develop computational design tools that enable control of recombinant gene translational activity in CHO cells. Through a combination of pulsed stable isotope labelling of amino acids in cell culture (pSILAC) and RNA-Seq based analysis of the CHO cell transcriptome we quantified the translational efficiency of \u3e 4000 mRNAs. Based on informatic reconstruction of CHO mRNAs (to include untranslated and coding sequences) we built and trained a gaussian process regression model using over 250 defined mRNA sequence features to enable validated in silico prediction of mRNA translational efficiency in CHO cells from mRNA sequence. Using this genome-scale empirical modeling we created a computational gene analysis and design platform that permits both prediction of the translational efficiency of natural and recombinant mRNAs in CHO cells and de novo design of synthetic mRNAs with predictable translational activity. This platform will be employed to (i) maximize the efficiency of recombinant mRNA translation for easy-to-express proteins, (ii) optimize the rate of mRNA translation for difficult-to-express proteins and (iii) control the stoichiometry of product synthesis in multigene expression systems

Detection and monitoring of high stress concentration zones induced by coal mining using numerical and microseismic method

Zones of high stress concentration induced by coal mining at a depth of 1250 meters in the Lorraine Collieries are detected and monitored using a combination of numerical and microseismic methods. Changes in the stress state induced by coal mining are estimated by means of numerical simulations. The areas of high stress concentration are located and monitored by local microseismic network. The study of microseismic activity recorded during mining made it possible to localise the zones of high stress concentration and validate the calculations done by numerical modelling. The results of this study hold out interesting prospects for using a combination of numerical modelling and microseismic monitoring for detecting, locating and monitoring of the zones prone to rockbursts

The quantitative proteomic response of Synechocystis sp. PCC6803 to phosphate acclimation.

BACKGROUND: Inorganic phosphate (Pi) is a critical nutrient for all life and is periodically limiting in marine and freshwater provinces, yet little is understood how organisms acclimate to fluctuations in Pi within their environment. To investigate whole cell adaptation, we grew Synechocystis sp. PCC6803, a model freshwater cyanobacterium, in 3%, and 0.3% inorganic phosphate (Pi) media. The cells were allowed to acclimate over 60 days, and cells were harvested for quantitative high throughput mass spectrometry-based proteomics using the iTRAQ™ labelling technology. RESULTS: In total, 120 proteins were identified, and 52 proteins were considered differentially abundant compared to the control. Alkaline phosphatase (APase) activities correlated significantly (p < 0.05) with observed relative PhoA abundances. PstS1 and PstS2 were both observed, yet PstS1 was not differentially more abundant than the control. Phycobilisome protein abundances appeared to be coordinated, and are significantly less abundant in 0.3% Pi than 3% Pi cultures. Also, the central metabolic cell function appears to have shifted towards the production of (NADPH) reducing energy and nucleotide sugars. CONCLUSIONS: This acclimation response bears strong similarity to the previously reported response to nitrogen deprivation within Synechocystis sp. PCC 6803. However, it also demonstrates some characteristics of desiccation stress, such as the regulation of fatty acids and increased abundance of rehydrin in the 3% Pi culture

Satisfiability, sequence niches, and molecular codes in cellular signaling

Biological information processing as implemented by regulatory and signaling networks in living cells requires sufficient specificity of molecular interaction to distinguish signals from one another, but much of regulation and signaling involves somewhat fuzzy and promiscuous recognition of molecular sequences and structures, which can leave systems vulnerable to crosstalk. This paper examines a simple computational model of protein-protein interactions which reveals both a sharp onset of crosstalk and a fragmentation of the neutral network of viable solutions as more proteins compete for regions of sequence space, revealing intrinsic limits to reliable signaling in the face of promiscuity. These results suggest connections to both phase transitions in constraint satisfaction problems and coding theory bounds on the size of communication codes

Reduced keratin expression in colorectal neoplasia and associated fields is reversible by diet and resection

Abstract Background Patients with adenomatous colonic polyps are at increased risk of developing further polyps suggesting field-wide alterations in cancer predisposition. The current study aimed to identify molecular alterations in the normal mucosa in the proximity of adenomatous polyps and to assess the modulating effect of butyrate, a chemopreventive compound produced by fermentation of dietary residues. Methods A cross-sectional study was undertaken in patients with adenomatous polyps: biopsy samples were taken from the adenoma, and from macroscopically normal mucosa on the contralateral wall to the adenoma and from the mid-sigmoid colon. In normal subjects biopsies were taken from the mid-sigmoid colon. Biopsies were frozen for proteomic analysis or formalin-fixed for immunohistochemistry. Proteomic analysis was undertaken using iTRAQ workflows followed by bioinformatics analyses. A second dietary fibre intervention study arm used the same endpoints and sampling strategy at the beginning and end of a high-fibre intervention. Results Key findings were that keratins 8, 18 and 19 were reduced in expression level with progressive proximity to the lesion. Lesional tissue exhibited multiple K8 immunoreactive bands and overall reduced levels of keratin. Biopsies from normal subjects with low faecal butyrate also showed depressed keratin expression. Resection of the lesion and elevation of dietary fibre intake both appeared to restore keratin expression level. Conclusion Changes in keratin expression associate with progression towards neoplasia, but remain modifiable risk factors. Dietary strategies may improve secondary chemoprevention. Trial registration number ISRCTN90852168. Keywords: ADENOMA, BUTYRATE, CYTOKERATINS, DIETARY FIBR

Evidence After Imputation for a Role of MICA Variants in Nonprogression and Elite Control of HIV Type 1 Infection

Past genome-wide association studies (GWAS) involving individuals with AIDS have mainly identified associations in the HLA region. Using the latest software, we imputed 7 million single-nucleotide polymorphisms (SNPs)/indels of the 1000 Genomes Project from the GWAS-determined genotypes of individuals in the Genomics of Resistance to Immunodeficiency Virus AIDS nonprogression cohort and compared them with those of control cohorts. The strongest signals were in MICA, the gene encoding major histocompatibility class I polypeptide-related sequence A (P = 3.31 × 10−12), with a particular exonic deletion (P = 1.59 × 10−8) in full linkage disequilibrium with the reference HCP5 rs2395029 SNP. Haplotype analysis also revealed an additive effect between HLA-C, HLA-B, and MICA variants. These data suggest a role for MICA in progression and elite control of human immunodeficiency virus type 1 infectio