| 1. |
- Sehat, Bita, et al.
(författare)
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SUMOylation Mediates the Nuclear Translocation and Signaling of the IGF-1 Receptor
- 2010
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 3:108
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein-1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues-Lys(1025), Lys(1100), and Lys(1120)-in the beta subunit of the receptor. Mutation of these SUMO-1 sites abolished the ability of IGF-1R to translocate to the nucleus and activate transcription, but did not alter its kinase-dependent signaling. Thus, we demonstrate a SUMOylation-mediated mechanism of IGF-1R signaling that has potential implications for gene regulation.
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| 2. |
- Sjöstrand, Joel, et al.
(författare)
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A Bayesian Method for Analyzing Lateral Gene Transfer
- 2014
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Ingår i: Systematic Biology. - : Oxford University Press (OUP). - 1063-5157 .- 1076-836X. ; 63:3, s. 409-420
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Tidskriftsartikel (refereegranskat)abstract
- Lateral gene transfer (LGT)uwhich transfers DNA between two non-vertically related individuals belonging to the same or different speciesuis recognized as a major force in prokaryotic evolution, and evidence of its impact on eukaryotic evolution is ever increasing. LGT has attracted much public attention for its potential to transfer pathogenic elements and antibiotic resistance in bacteria, and to transfer pesticide resistance from genetically modified crops to other plants. In a wider perspective, there is a growing body of studies highlighting the role of LGT in enabling organisms to occupy new niches or adapt to environmental changes. The challenge LGT poses to the standard tree-based conception of evolution is also being debated. Studies of LGT have, however, been severely limited by a lack of computational tools. The best currently available LGT algorithms are parsimony-based phylogenetic methods, which require a pre-computed gene tree and cannot choose between sometimes wildly differing most parsimonious solutions. Moreover, in many studies, simple heuristics are applied that can only handle putative orthologs and completely disregard gene duplications (GDs). Consequently, proposed LGT among specific gene families, and the rate of LGT in general, remain debated. We present a Bayesian Markov-chain Monte Carlo-based method that integrates GD, gene loss, LGT, and sequence evolution, and apply the method in a genome-wide analysis of two groups of bacteria: Mollicutes and Cyanobacteria. Our analyses show that although the LGT rate between distant species is high, the net combined rate of duplication and close-species LGT is on average higher. We also show that the common practice of disregarding reconcilability in gene tree inference overestimates the number of LGT and duplication events. [Bayesian; gene duplication; gene loss; horizontal gene transfer; lateral gene transfer; MCMC; phylogenetics.].
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| 3. |
- Tofigh, Ali, et al.
(författare)
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A global structural em algorithm for a model of cancer progression
- 2011
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Ingår i: Adv. Neural Inf. Process. Syst.: Annu. Conf. Neural Inf. Process. Syst., NIPS. - : Neural Information Processing Systems.
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Konferensbidrag (refereegranskat)abstract
- Cancer has complex patterns of progression that include converging as well as diverging progressional pathways. Vogelstein's path model of colon cancer was a pioneering contribution to cancer research. Since then, several attempts have been made at obtaining mathematical models of cancer progression, devising learning algorithms, and applying these to cross-sectional data. Beerenwinkel et al. provided, what they coined, EM-like algorithms for Oncogenetic Trees (OTs) and mixtures of such. Given the small size of current and future data sets, it is important to minimize the number of parameters of a model. For this reason, we too focus on tree-based models and introduce Hidden-variable Oncogenetic Trees (HOTs). In contrast to OTs, HOTs allow for errors in the data and thereby provide more realistic modeling. We also design global structural EM algorithms for learning HOTs and mixtures of HOTs (HOT-mixtures). The algorithms are global in the sense that, during the M-step, they find a structure that yields a global maximum of the expected complete log-likelihood rather than merely one that improves it. The algorithm for single HOTs performs very well on reasonable-sized data sets, while that for HOT-mixtures requires data sets of sizes obtainable only with tomorrow's more cost-efficient technologies.
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| 4. |
- Tofigh, Ali, et al.
(författare)
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Detecting LGTs using a novel probabilistic modelintegrating duplications, LGTs, losses, rate variation,and sequence evolution
- 2009
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The debate over the prevalence of lateral gene transfers (LGTs) has been intense.There is now to a large extent consensus around the view that LGT is an important evolutionary force as well as regarding its relative importance across species. This consensus relies, however, mainly on studies of individual gene families.Up until now, the gold standard for identifying LGTs has been phylogenetic methods where LGTs are inferred from incongruities between a species tree andan associated gene tree. Even in cases where there is evidence of LGT, several concerns have often been raised regarding the significance of the evidence. One common concern has been the possibility that other evolutionary events have caused the incongruities. Another has been the significance of the gene trees involved in the inference; there may for instance be alternative, almost equally likely, gene trees that do not provide evidence for LGT. Independently of these concerns, there has been a need for methods that can be used to quantitatively characterize the level of LGT among sets of species, but also for methods able to pinpoint where in the species tree LGTs have occurred.Here, we provide the first probabilistic model capturing gene duplication, LGT,gene loss, and point mutations with a relaxed molecular clock. We also provide allfundamental algorithms required to analyze a gene family relative to a given speciestree under this model. Our algorithms are based on Markov chain Monte Carlo(MCMC) methodology but build also on techniques from numerical analysis and involve dynamic programming (DP).
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| 5. |
- Tofigh, Ali, et al.
(författare)
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Inferring Duplications and Lateral Gene Transfers : An Algorithm for Parametric Tree Reconciliation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Prediction of the function of genes and their products is an increasingly important computational problem. The ability to correctly identify the historic relationship of homologous genes is essential for making accurate predictions.In 1970, Fitch made a distinction between paralogous and orthologous genes, its importance lying in the observation that genes are more likely to have similar functions when they have evolved from a common ancestral gene through speciation rather than duplication. Lateral gene transfer (LGT) is yet another important evolutionary event that creates copies of genes, and asour understanding of the importance and prevalence of LGT in evolution is deepening, there is a high demand for methods for detection of LGTs when reconstructing the evolutionary past of genes. In this paper, we present highly efficient and practical algorithms for treereconciliation that simultaneously consider both duplications and LGTs. Weallow costs to be associated with duplications and LGTs and develop methods for finding reconciliations of minimal total cost between species trees andgene trees. Moreover, we provide an efficient algorithm for parametric treereconciliation—a computational problem analogous to parametric sequencealignment. Experimental results on synthetic data indicate that our methodsare robust with high specificity and sensitivity.
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| 6. |
- Tofigh, Ali, et al.
(författare)
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Simultaneous Identification of Duplications and Lateral Gene Transfers
- 2011
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Ingår i: IEEE/ACM Transactions on Computational Biology & Bioinformatics. - 1545-5963 .- 1557-9964. ; 8:2, s. 517-535
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Tidskriftsartikel (refereegranskat)abstract
- The incongruency between a gene tree and a corresponding species tree can be attributed to evolutionary events such as gene duplication and gene loss. This paper describes a combinatorial model where a so-called DTL-scenario is used to explain the differences between a gene tree anda corresponding species tree taking into account gene duplications, gene losses, and lateral genetransfers (also known as horizontal gene transfers). The reasonable biological constraint that a lateralgene transfer may only occur between contemporary species leads to the notion of acyclic DTLscenarios.Parsimony methods are introduced by defining appropriate optimization problems. Weshow that finding most parsimonious acyclic DTL-scenarios is NP-complete. However, by droppingthe condition of acyclicity, the problem becomes tractable, and we provide a dynamic programmingalgorithm as well as a fixed-parameter-tractable algorithm for finding most parsimonious DTLscenarios.
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| 7. |
- Tofigh, Ali, 1977-
(författare)
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Using Trees to Capture Reticulate Evolution : Lateral Gene Transfers and Cancer Progression
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The historic relationship of species and genes are traditionally depicted using trees. However, not all evolutionary histories are adequately captured by bifurcating processes and an increasing amount of research is devoted towards using networks or network-like structures to capture evolutionary history. Lateral gene transfer (LGT) is a previously controversial mechanism responsible for non tree-like evolutionary histories, and is today accepted as a major force of evolution, particularly in the prokaryotic domain. In this thesis, we present models of gene evolution incorporating both LGTs and duplications, together with efficient computational methods for various inference problems. Specifically, we define a biologically sound combinatorial model for reconciliation of species and gene trees that facilitates simultaneous consideration of duplications and LGTs. We prove that finding most parsimonious reconciliations is NP-hard, but that the problem can be solved efficiently if reconciliations are not required to be acyclic—a condition that is satisfied when analyzing most real-world datasets. We also provide a polynomial-time algorithm for parametric tree reconciliation, a problem analogous to parametric sequence alignment, that enables us to study the entire space of optimal reconciliations under all possible cost schemes. Going beyond combinatorial models, we define the first probabilistic model of gene evolution incorporating a birth-death process generating duplications, LGTs, and losses, together with a relaxed molecular clock model of sequence evolution. Algorithms based on Markov chain Monte Carlo (MCMC) techniques, methods from numerical analysis, and dynamic programming are presented for various probability and parameter inference problems. Finally, we develop methods for analysis of cancer progression, a biological process with many similarities to the process of evolution. Cancer progresses by accumulation of harmful genetic aberrations whose patterns of emergence are graph-like. We develop a model of cancer progression based on trees, and mixtures thereof, that admits an efficient structural EM algorithm for finding Maximum Likelihood (ML) solutions from available cross-sectional data.
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