Mistranslation-induced protein misfolding as a dominant constraint on coding-sequence evolution

Strikingly consistent correlations between rates of coding-sequence evolution and gene expression levels are apparent across taxa, but the biological causes behind the selective pressures on coding-sequence evolution remain controversial. Here, we demonstrate conserved patterns of simple covariation between sequence evolution, codon usage, and mRNA level in E. coli, yeast, worm, fly, mouse, and human that suggest that all observed trends stem largely from a unified underlying selective pressure. In metazoans, these trends are strongest in tissues composed of neurons, whose structure and lifetime confer extreme sensitivity to protein misfolding. We propose, and demonstrate using a molecular-level evolutionary simulation, that selection against toxicity of misfolded proteins generated by ribosome errors suffices to create all of the observed covariation. The mechanistic model of molecular evolution that emerges yields testable biochemical predictions, calls into question the use of nonsynonymous-to-synonymous substitution ratios (Ka/Ks) to detect functional selection, and suggests how mistranslation may contribute to neurodegenerative disease.     

Adaptive evolution by optimizing expression levels in different environments

Organisms adapt to environmental changes through the fixation of mutations that enhance reproductive success. A recent study by Dekel and Alon demonstrated that Escherichia coli adapts to different growth conditions by fine-tuning protein levels, as predicted by a simple cost-benefit model. A study by Fong et al. showed that independent evolutionary trajectories lead to similar adaptive endpoints. Initial mutations on the path to adaptation altered the mRNA levels of numerous genes. Subsequent optimization through compensatory mutations restored the expression of most genes to baseline levels, except for a small set that retained differential levels of expression. These studies clarify how adaptation could occur by the alteration of gene expression.     

The p38 and Hog1 SAPKs control cell cycle progression in response to environmental stresses

In response to environmental stresses, cells need to activate an adaptive program to maximize cell progression and survival. Stress-activated protein kinases (SAPK) are key signal transduction kinases required to respond to stress. Prototypical members of SAPKs are the yeast Hog1 and mammalian p38. Upon stress, those enzymes play a critical role in mounting the adaptive responses to stress such as the regulation of metabolism and the control of gene expression. In addition, a major function of SAPKs in response to stress is to modulate cell cycle progression. In this review, we focus on the role of Hog1 and p38 in the control of cell cycle progression in response to environmental stresses.     

Need-Based Up-Regulation of Protein Levels in Response to Deletion of Their Duplicate Genes

Many duplicate genes maintain functional overlap despite divergence over long evolutionary time scales. Deleting one member of a paralogous pair often has no phenotypic effect, unless its paralog is also deleted. It has been suggested that this functional compensation might be mediated by active up-regulation of expression of a gene in response to deletion of its paralog. However, it is not clear how prevalent such paralog responsiveness is, nor whether it is hardwired or dependent on feedback from environmental conditions. Here, we address these questions at the genomic scale using high-throughput flow cytometry of single-cell protein levels in differentially labeled cocultures of wild-type and paralog-knockout Saccharomyces cerevisiae strains. We find that only a modest fraction of proteins (22 out of 202) show significant up-regulation to deletion of their duplicate genes. However, these paralog-responsive proteins match almost exclusively duplicate pairs whose overlapping function is required for growth. Moreover, media conditions that add or remove requirements for the function of a duplicate gene pair specifically eliminate or create paralog responsiveness. Together, our results suggest that paralog responsiveness in yeast is need-based: it appears only in conditions in which the gene function is required. Physiologically, such need-based responsiveness could provide an adaptive mechanism for compensation of genetic, environmental, or stochastic perturbations in protein abundance.     

石榴WRKY基因家族全基因组鉴定与表达分析

WRKY蛋白是一类在植物生长发育过程及生物与非生物胁迫过程中起重要调控作用的转录因子。该研究利用石榴全基因组数据,采用生物信息学的方法,对石榴WRKY转录因子家族成员蛋白理化性质、系统进化、基因结构、保守基序、顺式作用元件、蛋白互作及基因共表达和转录组表达模式进行系统分析。结果共鉴定出69个PgWRKY基因;分组鉴定和进化分析显示WRKY蛋白可分为Ⅰ、Ⅱ和Ⅲ共三大类型。顺式作用元件分析表明,PgWRKY基因广泛参与到非生物胁迫中;蛋白互作网络与共表达分析暗示PgWRKY基因在同一胁迫应答中可能作用一致并同时诱导表达;RNA-Seq数据分析表明,PgWRKY基因有一定的组织表达特异性,广泛参与植物营养、生殖生长以及根部逆境胁迫应答过程。     

PKA and Sch9 control a molecular switch important for the proper adaptation to nutrient availability

In the yeast Saccharomyces cerevisiae, PKA and Sch9 exert similar physiological roles in response to nutrient availability. However, their functional redundancy complicates to distinguish properly the target genes for both kinases. In this article, we analysed different phenotypic read-outs. The data unequivocally showed that both kinases act through separate signalling cascades. In addition, genome-wide expression analysis under conditions and with strains in which either PKA and/or Sch9 signalling was specifically affected, demonstrated that both kinases synergistically or oppositely regulate given gene targets. Unlike PKA, which negatively regulates stress-responsive element (STRE)- and post-diauxic shift (PDS)-driven gene expression, Sch9 appears to exert additional positive control on the Rim15-effector Gis1 to regulate PDS-driven gene expression. The data presented are consistent with a cyclic AMP (cAMP)-gating phenomenon recognized in higher eukaryotes consisting of a main gatekeeper, the protein kinase PKA, switching on or off the activities and signals transmitted through primary pathways such as, in case of yeast, the Sch9-controlled signalling route. This mechanism allows fine-tuning various nutritional responses in yeast cells, allowing them to adapt metabolism and growth appropriately.     

Multifaceted physiological response allows yeast to adapt to the loss of the signal recognition particle-dependent protein-targeting pathway

Translational control has recently been recognized as an important facet of adaptive responses to various stress conditions. We describe the adaptation response of the yeast Saccharomyces cerevisiae to the loss of one of two mechanisms to target proteins to the secretory pathway. Using inducible mutants that block the signal recognition particle (SRP) pathway, we find that cells demonstrate a physiological response to the loss of the SRP pathway that includes specific changes in global gene expression. Upon inducing the loss of the SRP pathway, SRP-dependent protein translocation is initially blocked, and cell growth is considerably slowed. Concomitantly, gene expression changes include the induction of heat shock genes and the repression of protein synthesis genes. Remarkably, within hours, the efficiency of protein sorting improves while cell growth remains slow in agreement with the persistent repression of protein synthesis genes. Our results suggest that heat shock gene induction serves to protect cells from mislocalized precursor proteins in the cytosol, whereas reduced protein synthesis helps to regain efficiency in protein sorting by reducing the load on the protein translocation apparatus. Thus, we suggest that cells trade speed in cell growth for fidelity in protein sorting to adjust to life without SRP.     

Proteomic changes in response to potassium starvation in the extremophilic yeast Debaryomyces hansenii

In this work, we performed for the first time a proteomic approach to the processes induced by long-term potassium starvation in the halotolerant yeast Debaryomyces hansenii. The proteomic profile under this ionic stress conditions shows that important changes in gene expression take place as an adaptive response. We found a significant protein expression repression as well as metabolic changes such as the inhibition of the upper part of the glycolysis, the amino acid synthesis, and the Krebs cycle. On the other hand, genes related to stress responses, protein degradation, and sterols synthesis were upregulated in response to potassium deprivation. The findings in this study provide important information about how this particular yeast copes with ionic stress at molecular levels, which might further enrich the global understanding of salt tolerance processes in eukaryal systems and moreover highlighting the importance of the 'omics' approaches as a complement to the classical physiological studies.     

植物免疫应答过程中 Ca2 ＋及 CaM/CML 的功能

钙离子是一个多功能的第二信使,在植物响应各种生理刺激时,Ca2＋参与调节植物的多种生长发育和胁迫适应过程。在这些过程中,Ca2＋信号带有特异性标签,通过Ca2＋结合蛋白及其下游靶蛋白感知不同刺激并翻译成响应的细胞反应。钙调素（CaM）和钙调素类蛋白（CML）是Ca2＋主要感受器,通过调节不同靶蛋白的活性调控多种细胞功能。最近在植物对抗病原菌的防卫反应中有关Ca2＋／CaM信号转导系统的研究取得了一定进展。重点关注植物免疫应答过程中受CaM／CML调控的信号组分的研究,包括参与Ca2＋信号产生和Ca2＋依赖的表达基因组分调控。     

Constraints on the evolution of adaptive phenotypic plasticity in plants

The high potential fitness benefit of phenotypic plasticity tempts us to expect phenotypic plasticity as a frequent adaptation to environmental heterogeneity. Examples of proven adaptive plasticity in plants, however, are scarce and most plastic responses actually may be 'passive' rather than adaptive. This suggests that frequently requirements for the evolution of adaptive plasticity are not met or that such evolution is impeded by constraints. Here we outline requirements and potential constraints for the evolution of adaptive phenotypic plasticity, identify open questions, and propose new research approaches. Important open questions concern the genetic background of plasticity, genetic variation in plasticity, selection for plasticity in natural habitats, and the nature and occurrence of costs and limits of plasticity. Especially promising tools to address these questions are selection gradient analysis, meta-analysis of studies on genotype-by-environment interactions, QTL analysis, cDNA-microarray scanning and quantitative PCR to quantify gene expression, and two-dimensional gel electrophoresis to quantify protein expression. Studying plasticity along the pathway from gene expression to the phenotype and its relationship with fitness will help us to better understand why adaptive plasticity is not more universal, and to more realistically predict the evolution of plastic responses to environmental change.     

De Novo Evolution of Complex, Global and Hierarchical Gene Regulatory Mechanisms

Gene regulatory networks exhibit complex, hierarchical features such as global regulation and network motifs. There is much debate about whether the evolutionary origins of such features are the results of adaptation, or the by-products of non-adaptive processes of DNA replication. The lack of availability of gene regulatory networks of ancestor species on evolutionary timescales makes this a particularly difficult problem to resolve. Digital organisms, however, can be used to provide a complete evolutionary record of lineages. We use a biologically realistic evolutionary model that includes gene expression, regulation, metabolism and biosynthesis, to investigate the evolution of complex function in gene regulatory networks. We discover that: (i) network architecture and complexity evolve in response to environmental complexity, (ii) global gene regulation is selected for in complex environments, (iii) complex, inter-connected, hierarchical structures evolve in stages, with energy regulation preceding stress responses, and stress responses preceding growth rate adaptations and (iv) robustness of evolved models to mutations depends on hierarchical level: energy regulation and stress responses tend not to be robust to mutations, whereas growth rate adaptations are more robust and non-lethal when mutated. These results highlight the adaptive and incremental evolution of complex biological networks, and the value and potential of studying realistic in silico evolutionary systems as a way of understanding living systems.     

Salt stress and hyperosmotic stress regulate the expression of different sets of genes in Synechocystis sp. PCC 6803.

Acclimation of microorganisms to environmental stress is closely related to the expression of various genes. We report here that salt stress and hyperosmotic stress have different effects on the cytoplasmic volume and gene expression in Synechocystis sp. PCC 6803. DNA microarray analysis indicated that salt stress strongly induced the genes for some ribosomal proteins. Hyperosmotic stress strongly induced the genes for 3-ketoacyl-acyl carrier protein reductase and rare lipoprotein A. Genes whose expression was induced both by salt stress and by hyperosmotic stress included those for heat-shock proteins and the enzymes for the synthesis of glucosylglycerol. We also found that each kind of stress induced a number of genes for proteins of unknown function. Our findings suggest that Synechocystis recognizes salt stress and hyperosmotic stress as different stimuli, although mechanisms common to the responses to each form of stress might also contribute to gene expression.     

Quantification of mRNA and protein and integration with protein turnover in a bacterium

Biological function and cellular responses to environmental perturbations are regulated by a complex interplay of DNA, RNA, proteins and metabolites inside cells. To understand these central processes in living systems at the molecular level, we integrated experimentally determined abundance data for mRNA, proteins, as well as individual protein half‐lives from the genome‐reduced bacterium Mycoplasma pneumoniae. We provide a fine‐grained, quantitative analysis of basic intracellular processes under various external conditions. Proteome composition changes in response to cellular perturbations reveal specific stress response strategies. The regulation of gene expression is largely decoupled from protein dynamics and translation efficiency has a higher regulatory impact on protein abundance than protein turnover. Stochastic simulations using in vivo data show how low translation efficiency and long protein half‐lives effectively reduce biological noise in gene expression. Protein abundances are regulated in functional units, such as complexes or pathways, and reflect cellular lifestyles. Our study provides a detailed integrative analysis of average cellular protein abundances and the dynamic interplay of mRNA and proteins, the central biomolecules of a cell.