The chloroplast, a photosynthetic organelle found in all plant and algae species, originates from an ancient event in which a cyanobacterium was engulfed by a larger eukaryote. Thus, modern chloroplasts still harbor a bacterial-like... more
The chloroplast, a photosynthetic organelle found in all plant and algae species, originates from an ancient event in which a cyanobacterium was engulfed by a larger eukaryote. Thus, modern chloroplasts still harbor a bacterial-like genome and carry out all stages of gene expression, including mRNA translation by a 70S ribosome. However, the Shine-Dalgarno model, which predominantly regulates translation initiation by base-pairing between the ribosomal RNA and the mRNA in model bacteria genera, was reported to have ambiguous effects on chloroplast gene expression. Here we show that while the Shine-Dalgarno motif is clearly conserved in proteobacterial mRNAs, its general absence from chloroplast mRNAs is observed in cyanobacteria as well, promoting the idea that the evolutionary process of reducing the centrality of the Shine-Dalgarno mechanism began well before plastid endosymbiosis. As plastid ribosomal RNA anti-Shine-Dalgarno elements are highly similar to their bacterial counterp...
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The transcript is populated with numerous overlapping codes that regulate all steps of gene expression. Deciphering these codes is very challenging due to the large number of variables involved, the non-modular nature of the codes, biases... more
The transcript is populated with numerous overlapping codes that regulate all steps of gene expression. Deciphering these codes is very challenging due to the large number of variables involved, the non-modular nature of the codes, biases and limitations in current experimental approaches, our limited knowledge in gene expression regulation across the tree of life, and other factors. In recent years, it has been shown that computational modeling and algorithms can significantly accelerate the discovery of novel gene expression codes. Here, we briefly summarize the latest developments and different approaches in the field.
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Background mRNA can form local secondary structure within the protein-coding sequence, and the strength of this structure is thought to influence gene expression regulation. Previous studies suggest that secondary structure strength may... more
Background mRNA can form local secondary structure within the protein-coding sequence, and the strength of this structure is thought to influence gene expression regulation. Previous studies suggest that secondary structure strength may be maintained under selection, but the details of this phenomenon are not well understood. Results We perform a comprehensive study of the selection on local mRNA folding strengths considering variation between species across the tree of life. We show for the first time that local folding strength selection tends to follow a conserved characteristic profile in most phyla, with selection for weak folding at the two ends of the coding region and for strong folding elsewhere in the coding sequence, with an additional peak of selection for strong folding located downstream of the start codon. The strength of this pattern varies between species and organism groups, and we highlight contradicting cases. To better understand the underlying evolutionary proc...
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In many important cellular processes, including mRNA translation, gene transcription, phosphotransfer, and intracellular transport, biological "particles" move along some kind of "tracks". The motion of these particles... more
In many important cellular processes, including mRNA translation, gene transcription, phosphotransfer, and intracellular transport, biological "particles" move along some kind of "tracks". The motion of these particles can be modeled as a one-dimensional movement along an ordered sequence of sites. The biological particles (e.g., ribosomes or RNAPs) have volume and cannot surpass one another. In some cases, there is a preferred direction of movement along the track, but in general the movement may be bidirectional, and furthermore the particles may attach or detach from various regions along the tracks. We derive a new deterministic mathematical model for such transport phenomena that may be interpreted as a dynamic mean-field approximation of an important model from mechanical statistics called the asymmetric simple exclusion process (ASEP) with Langmuir kinetics. Using tools from the theory of monotone dynamical systems and contraction theory we show that the m...
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Viruses undergo extensive evolutionary selection for efficient replication which effects, among others, their codon distribution. In the current study, we aimed at understanding the way evolution shapes the codon distribution in early vs.... more
Viruses undergo extensive evolutionary selection for efficient replication which effects, among others, their codon distribution. In the current study, we aimed at understanding the way evolution shapes the codon distribution in early vs. late viral genes in terms of their expression during different stages in the viral replication cycle. To this end we analyzed 14 bacteriophages and 11 human viruses with available information about the expression phases of their genes. We demonstrated evidence of selection for distinct composition of synonymous codons in early and late viral genes in 50% of the analyzed bacteriophages. Among others, this phenomenon may be related to the time specific adaptation of the viral genes to the translation efficiency factors involved at different bacteriophage developmental stages. Specifically, we showed that the differences in codon composition in different temporal gene groups cannot be explained only by phylogenetic proximities between the analyzed bac...
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Translation initiation in prokaryotes is affected by the mRNA folding and interaction of the ribosome binding site with the ribosomal RNA. The elongation rate is affected, among other factors, by the local biophysical properties of the... more
Translation initiation in prokaryotes is affected by the mRNA folding and interaction of the ribosome binding site with the ribosomal RNA. The elongation rate is affected, among other factors, by the local biophysical properties of the coding regions, the decoding rates of different codons, and the interactions among ribosomes. Currently, there is no comprehensive biophysical model of translation that enables the prediction of mRNA translation dynamics based only on the transcript sequence and while considering all of these fundamental aspects of translation. In this study, we provide, for the first time, a computational simulative biophysical model of both translation initiation and elongation with all aspects mentioned above. We demonstrate our model performance and advantages focusing on Escherichia coli genes. We further show that the model enables prediction of translation rate, protein levels, and ribosome densities. In addition, our model enables quantifying the effect of sil...
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The two major steps of gene expression are transcription and translation. While hundreds of studies regarding the effect of sequence features on the translation elongation process have been published, very few connect sequence features to... more
The two major steps of gene expression are transcription and translation. While hundreds of studies regarding the effect of sequence features on the translation elongation process have been published, very few connect sequence features to the transcription elongation rate. We suggest, for the first time, that short transcript sub-sequences have a typical effect on RNA polymerase (RNAP) speed: we show that nucleotide 5-mers tend to have typical RNAP speed (or transcription rate), which is consistent along different parts of genes and among different groups of genes with high correlation. We also demonstrate that relative RNAP speed correlates with mRNA levels of endogenous and heterologous genes. Furthermore, we show that the estimated transcription and translation elongation rates correlate in endogenous genes. Finally, we demonstrate that our results are consistent for different high resolution experimental measurements of RNAP densities. These results suggest for the first time th...
Research Interests: Genetics and RNA biology
Various species of microalgae have recently emerged as promising host-organisms for use in biotechnology industries due to their unique properties. These include efficient conversion of sunlight into organic compounds, the ability to grow... more
Various species of microalgae have recently emerged as promising host-organisms for use in biotechnology industries due to their unique properties. These include efficient conversion of sunlight into organic compounds, the ability to grow in extreme conditions and the occurrence of numerous post-translational modification pathways. However, the inability to obtain high levels of nuclear heterologous gene expression in microalgae hinders the development of the entire field. To overcome this limitation, we analyzed different sequence optimization algorithms while studying the effect of transcript sequence features on heterologous expression in the model microalga Chlamydomonas reinhardtii, whose genome consists of rare features such as a high GC content. Based on the analysis of genomic data, we created eight unique sequences coding for a synthetic ferredoxin-hydrogenase enzyme, used here as a reporter gene. Following in silico design, these synthetic genes were transformed into the C...
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Ribosome queuing is a fundamental phenomenon suggested to be related to topics such as genome evolution, synthetic biology, gene expression regulation, intracellular biophysics, and more. However, this phenomenon hasn't been... more
Ribosome queuing is a fundamental phenomenon suggested to be related to topics such as genome evolution, synthetic biology, gene expression regulation, intracellular biophysics, and more. However, this phenomenon hasn't been quantified yet at a genomic level. Nevertheless, methodologies for studying translation (e.g. ribosome footprints) are usually calibrated to capture only single ribosome protected footprints (mRPFs) and thus limited in their ability to detect ribosome queuing. On the other hand, most of the models in the field assume and analyze a certain level of queuing. Here we present an experimental-computational approach for studying ribosome queuing based on sequencing of RNA footprints extracted from pairs of ribosomes (dRPFs) using a modified ribosome profiling protocol. We combine our approach with traditional ribosome profiling to generate a detailed profile of ribosome traffic. The data are analyzed using computational models of translation dynamics. The approach...
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During mRNA translation, several ribosomes attach to the same mRNA molecule simultaneously translating it into a protein. This pipelining increases the protein translation rate. A natural and important question is what ribosomal density... more
During mRNA translation, several ribosomes attach to the same mRNA molecule simultaneously translating it into a protein. This pipelining increases the protein translation rate. A natural and important question is what ribosomal density maximizes the protein translation rate. Using mathematical models of ribosome flow along both a linear and a circular mRNA molecules we prove that typically the steady-state protein translation rate is maximized when the ribosomal density is one half of the maximal possible density. We discuss the implications of our results to endogenous genes under natural cellular conditions and also to synthetic biology.
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ABSTRACT Co-evolution is the process in which a set of orthologs exhibits a similar or correlative pattern of evolution. Co-evolution is a powerful way to learn about the functional interdependencies between sets of genes and cellular... more
ABSTRACT Co-evolution is the process in which a set of orthologs exhibits a similar or correlative pattern of evolution. Co-evolution is a powerful way to learn about the functional interdependencies between sets of genes and cellular functions, about their complementary and backup relations, and more generally, for answering fundamental questions about the evolution of biological systems. Orthologs that exhibit strong signal of co-evolution in part of the evolutionary tree may show mild signal of co-evolution in other parts of the tree. The major reasons for this phenomenon are noise in the biological input, genes that gain or lose functions, and the fact that some measures of co-evolution relate to rare events such as positive evolution. Previous works in the field dealt with the problem of finding sets of genes that co-evolved along an entire underlying phylogenetic tree, without considering the fact that often co-evolution is local. In this work, we describe a new set of biological problems that are related to finding patterns of local co-evolution. We discuss their computational complexity and design algorithms for solving them. These algorithms outperform other bi-clustering methods as they are designed specifically for solving the set of problems mentioned above. We use our approach to trace the co-evolution of fungal and Eukaryotic genes at a high resolution across the different parts of the corresponding phylogenetic trees. Our analysis shows that local co-evolution is a wide-scale phenomenon.
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A single mammalian cell includes an order of 10 4 –10 5 mRNA molecules and as many as 10 5 –10 6 ribosomes. Large-scale simultaneous mRNA translation induces correlations between the mRNA molecules, as they all compete for the finite pool... more
A single mammalian cell includes an order of 10 4 –10 5 mRNA molecules and as many as 10 5 –10 6 ribosomes. Large-scale simultaneous mRNA translation induces correlations between the mRNA molecules, as they all compete for the finite pool of available ribosomes. This has important implications for the cell's functioning and evolution. Developing a better understanding of the intricate correlations between these simultaneous processes, rather than focusing on the translation of a single isolated transcript, should help in gaining a better understanding of mRNA translation regulation and the way elongation rates affect organismal fitness. A model of simultaneous translation is specifically important when dealing with highly expressed genes, as these consume more resources. In addition, such a model can lead to more accurate predictions that are needed in the interconnection of translational modules in synthetic biology. We develop and analyse a general dynamical model for large-sc...
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Using the dynamic mean-field approximation of the totally asymmetric simple exclusion process (TASEP), we investigate the effect of small changes in the initiation, elongation, and termination rates along the mRNA strand on the... more
Using the dynamic mean-field approximation of the totally asymmetric simple exclusion process (TASEP), we investigate the effect of small changes in the initiation, elongation, and termination rates along the mRNA strand on the steady-state protein translation rate. We show that the sensitivity of mRNA translation is equal to the sensitivity of the maximal eigenvalue of a symmetric, nonnegative, tridiagonal, and irreducible matrix. This leads to new analytical results as well as efficient numerical schemes that are applicable for large-scale models. Our results show that in the usual endogenous case, when initiation is more rate-limiting than elongation, the sensitivity of the translation rate to small mutations rapidly increases towards the 5' end of the ORF. When the initiation rate is high, as may be the case for highly expressed and/or heterologous optimized genes, the maximal sensitivity is with respect to the elongation rates at the middle of the mRNA strand. We also show that the maximal possible effect of a small increase/decrease in any of the rates along the mRNA is an increase/decrease of the same magnitude in the translation rate. These results are in agreement with previous molecular evolutionary and synthetic biology experimental studies.
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RNA splicing is the central process of intron removal in eukaryotes known to regulate various cellular functions such as growth, development, and response to external signals. The canonical sequences indicating the splicing sites needed... more
RNA splicing is the central process of intron removal in eukaryotes known to regulate various cellular functions such as growth, development, and response to external signals. The canonical sequences indicating the splicing sites needed for intronic boundary recognition are well known. However, the roles and evolution of the local folding of intronic and exonic sequence features adjacent to splice sites has yet to be thoroughly studied. Here, focusing on four fungi (Saccharomyces cerevisiae, Schizosaccharomyces pombe, Aspergillus nidulans, and Candida albicans), we performed for the first time a comprehensive high-resolution study aimed at characterizing the encoding of intronic splicing efficiency in pre-mRNA transcripts and its effect on intron evolution. Our analysis supports the conjecture that pre-mRNA local folding strength at intronic boundaries is under selective pressure, as it significantly affects splicing efficiency. Specifically, we show that in the immediate region of ...
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bservable inherited characteristics of an individual (what we see) is called phenotype. . The genetic constitution, which is the particular set of alleles inherited by the individual (what it inherits) is its genotype. . Whenever a single... more
bservable inherited characteristics of an individual (what we see) is called phenotype. . The genetic constitution, which is the particular set of alleles inherited by the individual (what it inherits) is its genotype. . Whenever a single allele determines the phenotype (even if present in one homologous chromosome), this allele is called dominant. Dominant disease alleles are rare. . In contrast recessive allele is one that produces a particular phenotype only if it is present in both homologous chromosomes. . The chance of an allele to produce the expected phenotype is called penetrance. . The configuration of particular alleles on homologous chromosomes is called phase. For example, in figure 15.1 the phase is AB/ab. 15.1.3 Mendel's Laws First Law: Segregation Two alleles segregate from each other in gametes. Each gamete takes each allele with probability of 0.5. Second Law: Independent Assortment Genes of di#erent traits are inherited independently. Aviv Univ. Third
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ABSTRACT Gene translation is a central cellular process in all living organisms including humans. Thus, predictive modeling of this process, based on various patient specific genomic and cellular features, should have important... more
ABSTRACT Gene translation is a central cellular process in all living organisms including humans. Thus, predictive modeling of this process, based on various patient specific genomic and cellular features, should have important applications in the diagnosis and understanding of various diseases. In this chapter we survey the recent advances in modeling gene translation and its potential clinical applications.
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... (Extended Abstract) Shlomi Reuveni1,2,⋆ , Isaac Meilijson1, Martin Kupiec3, Eytan Ruppin4,5, and Tamir Tuller6,7,⋆,⋆⋆ ... Science 324, 218223 (2009) 3. dos Reis, M., et al.: Solving the riddle of codon usage preferences: a test for... more
... (Extended Abstract) Shlomi Reuveni1,2,⋆ , Isaac Meilijson1, Martin Kupiec3, Eytan Ruppin4,5, and Tamir Tuller6,7,⋆,⋆⋆ ... Science 324, 218223 (2009) 3. dos Reis, M., et al.: Solving the riddle of codon usage preferences: a test for trans-lational selection. Nucleic Acids Res. ...
... i,pars(Si∪z,Ti) and let Cd S∪z,F = ∑ i Cd T i,pars(Si∪z,Ti) . Then 2 − log(kc)·pars(S∪z,F )−Cd SUz,F ≤ Pr(S, lh = z|p ∗ ,F) ≤ 2 − log(kc)·pars(S∪z,F )−Cu SUz,F . Corollary 3. Let T1 and T2 be two subforests with the same ...
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ABSTRACT Horizontal Gene Transfer (HGT) is the event of transferring genetic material from one lineage in the evolutionary tree to a different lineage. HGT plays a major role in bacterial genome diversification and is a significant... more
ABSTRACT Horizontal Gene Transfer (HGT) is the event of transferring genetic material from one lineage in the evolutionary tree to a different lineage. HGT plays a major role in bacterial genome diversification and is a significant mechanism by which bacteria develop resistance to antibiotics. Although the prevailing assumption is of complete HGT, cases of partial HGT (which are also named chimeric HGT) where only part of a gene is horizontally transferred, have also been reported, albeit less frequently. In this work we suggest a new probabilistic model for analyzing and modeling phylogenetic networks, the NET-HMM. This new model captures the biologically realistic assumption that neighboring sites of DNA or amino acid sequences are not independent, which increases the accuracy of the inference. The model describes the phylogenetic network as a Hidden Markov Model (HMM), where each hidden state is related to one of the network’s trees. One of the advantages of the NET-HMM is its ability to infer partial HGT as well as complete HGT. We describe the properties of the NET-HMM, devise efficient algorithms for solving a set of problems related to it, and implement them in software. We also provide a novel complementary significance test for evaluating the fitness of a model (NET-HMM) to a given data set. Using NET-HMM we are able to answer interesting biological questions, such as inferring the length of partial HGT’s and the affected nucleotides in the genomic sequences, as well as inferring the exact location of HGT events along the tree branches. These advantages are demonstrated through the analysis of synthetical inputs and two different biological inputs.
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Bayesian networks are widely used for modelling gene networks. We investigate the problem of expanding a given Bayesian network by adding a hidden node – a node on which no experimental data are given. Finding a good expansion (a new... more
Bayesian networks are widely used for modelling gene networks. We investigate the problem of expanding a given Bayesian network by adding a hidden node – a node on which no experimental data are given. Finding a good expansion (a new hidden node and its neighborhood) can point to regions where the model is not rich enough, and help locate new,
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ABSTRACT Gene expression is a fundamental cellular process by which proteins are synthesized based on the information coded in the genes. Understanding, modeling and engineering this process have both important biotechnological... more
ABSTRACT Gene expression is a fundamental cellular process by which proteins are synthesized based on the information coded in the genes. Understanding, modeling and engineering this process have both important biotechnological applications and contributions to basic life science. In this paper I describe the flow models - a new approach for computationally modeling the biophysics of gene expression. The flow models can describe various stages of gene expression in a computationally efficient manner; in addition, they can be more readily analyzed mathematically than alternative models. Thus, these models provide a comprehensive framework for in-silico engineering of gene expression.
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The asymmetric simple exclusion process (ASEP) is an important model from statistical physics describing particles that hop randomly from one site to the next along an ordered lattice of sites, but only if the next site is empty. ASEP has... more
The asymmetric simple exclusion process (ASEP) is an important model from statistical physics describing particles that hop randomly from one site to the next along an ordered lattice of sites, but only if the next site is empty. ASEP has been used to model and analyze numerous multiagent systems with local interactions including the flow of ribosomes along the mRNA strand. In ASEP with periodic boundary conditions a particle that hops from the last site returns to the first one. The mean field approximation of this model is referred to as the ribosome flow model on a ring (RFMR). The RFMR may be used to model both synthetic and endogenous gene expression regimes. We analyze the RFMR using the theory of monotone dynamical systems. We show that it admits a continuum of equilibrium points and that every trajectory converges to an equilibrium point. Furthermore, we show that it entrains to periodic transition rates between the sites. We describe the implications of the analysis results to understanding and engineering cyclic mRNA translation in-vitro and in-vivo.
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We describe a new approach for combining and com-paring: 1) The information that gene expression mea-surements represent. 2) Prior biological knowledge (that is modeled as a weighted graph). Our approach includes translating the prior... more
We describe a new approach for combining and com-paring: 1) The information that gene expression mea-surements represent. 2) Prior biological knowledge (that is modeled as a weighted graph). Our approach includes translating the prior biological knowledge to a Bayesian ...
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... [Extended Abstract] Tamir Tuller1,⋆, Efrat Oron2, Erez Makavy1, Daniel A. Chamovitz2, and Benny Chor1 ... Let dS : M×M→ R≥0, where M is the space of datasets over S, denote a measure for the dissimilarity of the expression pattern of... more
... [Extended Abstract] Tamir Tuller1,⋆, Efrat Oron2, Erez Makavy1, Daniel A. Chamovitz2, and Benny Chor1 ... Let dS : M×M→ R≥0, where M is the space of datasets over S, denote a measure for the dissimilarity of the expression pattern of the gene set S in M1 vs. M2. ...