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).
QC 20100812
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).
QC 20100812
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.
QC 20100812 Uppdaterad från submitted till published(20110301)
Published
QC 20100812 Uppdaterad från submitted till published(20110301)
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.
Published
Cancer has complex patterns of progression that include converging as well as diverging progressional pathways. Vogelstein’s path model of colon cancer was clearly a pioneering contribution to cancer ...research. Since then, several attempts have been made at obtaining mathematical models of cancer progression, devising training algorithms,and applying these to cross-sectional data.Beerenwinkel et al. provided, what they coined, EM-like algorithms for OncogeneticTrees (OTs) and mixtures of such. Given the small size of current and future datasets, it is important to minimize the number of parameters of a model. For this reason,also we 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 tomorrows more cost efficient technologies. To facilitate analysis of complex cytogenetic data sets requiring more than one HOT, we devise a decomposition strategy based on PrincipalComponent Analysis and train parameters on a colon cancer data set. The method so obtained is then successfully applied to kidney cancer.
QC 20100812
Cancer has complex patterns of progression that include converging as well as diverging progressional pathways. Vogelstein’s path model of colon cancer was clearly a pioneering contribution to cancer research. Since then, several attempts have been made at obtaining mathematical models of cancer progression, devising training algorithms,and applying these to cross-sectional data.Beerenwinkel et al. provided, what they coined, EM-like algorithms for OncogeneticTrees (OTs) and mixtures of such. Given the small size of current and future datasets, it is important to minimize the number of parameters of a model. For this reason,also we 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 tomorrows more cost efficient technologies. To facilitate analysis of complex cytogenetic data sets requiring more than one HOT, we devise a decomposition strategy based on PrincipalComponent Analysis and train parameters on a colon cancer data set. The method so obtained is then successfully applied to kidney cancer.
QC 20100812
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.
QC 20100812
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.
QC 20100812
Detektion av kemiska ämnen anses allmänt vara den äldsta sensoriska förmågan. De kemiska sinnena, lukt och smak, utvecklades för att upptäcka och analysera kemisk information i form av luft- eller ...vattenburna ämnen, för att hitta mat och partners, och för att undvika fara. Luktsystemet är organiserat efter samma principer hos nästan alla djurarter, insekter såväl som däggdjur. Troligen beror likheterna på parallell evolution – samma organisation verkar ha uppstått mer än en gång. Därför antas det ofta att luktsystemet är nära optimalt anpassat för sina arbetsuppgifter.Paradoxalt nog är luktsystemets arbetsprinciper ännu inte väl kända, även om flera banbrytande framsteg gjorts de senaste decennierna. Det mest välkända är nog upptäckten av genfamiljen av luktreceptorer, som tillkännagavs 1991 av Linda Buck och Rikard Axel. För detta och efterföljande arbete belönades de med Nobelpriset år 2004. Upptäckten har varit mycket värdefull för både experimentalister och teoretiker, och är grunden för vår nuvarande förståelse av luktsystemet. Luktsystemet har länge varit ett fokus för vetenskapligt intresse inom flera fält, experimentella såväl som teoretiska, och har ofta använts som ett modellsystem. Och ända sedan fältet beräkningsneurobiologi grundades har luktsystemet undersökts genom datormodellering. I denna avhandling presenterar jag flera ansatser till biologiskt realistiskaberäkningsmodeller av luktsystemet, med tonvikt på de tidigare delarna av ryggradsdjurens luktsystem – luktreceptorceller och luktbulben. Jag har undersökt beteendet hos enzymet CaMKII, som anses vara kritiskt viktigt för adaptation (undertryckning av ständigt närvarande luktstimuli) i luktsystemet, i en biokemisk modell. Genom att konstruera flera olika stora modeller av luktbulben har jag visat att storleken på luktbulbens cellnätverk påverkar dess förmåga att behandla brusig information. Genom att ta hänsyn till nervcellernas rapporterade variationer i geometriska, elektriska och receptor-beroende karaktärsdrag har jag lyckats modellera svarsfrekvenserna från en population av luktreceptorceller. Jag har använt denna modell för att hitta de nyckelprinciper som styr huvuddelen av luktreceptorneuron-populationens svar, ochundersökt några av de tänkbara konsekvenserna av dessa nyckelprinciper i efterföljande studier av luktreceptorneuron-populationen och luktbulben – det vi kallar ”fuzzy concentration coding”-hypotesen.
QC20100723
Härtill 5 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2010
Teknologie doktorsexamen
D3, Lindstedtsvägen 5, Stockholm
Chemical sensing is believed to be the oldest sensory ability. The chemical senses, olfaction and gustation, developed to detect and analyze information in the form of air- or waterborne chemicals, to find food and mates, and to avoid danger. The organization of the olfactory system follows the same principles in almost all living animals, insects as well as mammals. Likely, the similarities are due to parallel evolution – the same type of organisation seems to have arisen more than once. Therefore, the olfactory system is often assumed to be close to optimally designed for its tasks.Paradoxically, the workings of the olfactory system are not yet well known,although several milestone discoveries have been made during the last decades. The most well-known is probably the disovery of the olfactory receptor gene family,announced in 1991 by Linda Buck and Richard Axel. For this and subsequent work, they were awarded a Nobel Prize Award in 2004. This achievement has been of immense value for both experimentalists and theorists, and forms the basis of the current understanding of olfaction. The olfactory system has long been a focus for scientific interest within several fields, both experimental and theoretical, and it has often been used asa model system. And ever since the field of computational neuroscience was founded, the functions of the olfactory system have been investigated through computational modelling. In this thesis, I present several approaches to biologically realistic computational models of parts of the olfactory system, with an emphasis on the earlier stages of the vertebrate olfactory system – olfactory receptor neurons (ORNs) and the olfactory bulb (OB). I have investigated the behaviour of the enzyme CaMKII, which is known to be critical for olfactory adaptation (suppression of constant odour stimuli) in the ORN, using a biochemical model. By constructing several OB models of different size, I have shown that the size of the OB network has an impact on its ability to process noisy information. Taking into account the reported variability of geometrical, electrical and receptor-dependent neuronal characteristics, I have been able to model the frequency response of a population of ORNs. I have used this model to find the key properties that govern most of the ORN population’s response, and investigated some of the possible implications of these key properties in subsequent studies of the ORN population and the OB – what we call the fuzzy concentration coding hypothesis.
degree of Doctor in Technology
Chemical sensing is believed to be the oldest sensory ability. The chemical senses, olfaction and gustation, developed to detect and analyze information in the form of air- or waterborne chemicals, to find food and mates, and to avoid danger. The organization of the olfactory system follows the same principles in almost all living animals, insects as well as mammals. Likely, the similarities are due to parallel evolution – the same type of organisation seems to have arisen more than once. Therefore, the olfactory system is often assumed to be close to optimally designed for its tasks.Paradoxically, the workings of the olfactory system are not yet well known,although several milestone discoveries have been made during the last decades. The most well-known is probably the disovery of the olfactory receptor gene family,announced in 1991 by Linda Buck and Richard Axel. For this and subsequent work, they were awarded a Nobel Prize Award in 2004. This achievement has been of immense value for both experimentalists and theorists, and forms the basis of the current understanding of olfaction. The olfactory system has long been a focus for scientific interest within several fields, both experimental and theoretical, and it has often been used asa model system. And ever since the field of computational neuroscience was founded, the functions of the olfactory system have been investigated through computational modelling. In this thesis, I present several approaches to biologically realistic computational models of parts of the olfactory system, with an emphasis on the earlier stages of the vertebrate olfactory system – olfactory receptor neurons (ORNs) and the olfactory bulb (OB). I have investigated the behaviour of the enzyme CaMKII, which is known to be critical for olfactory adaptation (suppression of constant odour stimuli) in the ORN, using a biochemical model. By constructing several OB models of different size, I have shown that the size of the OB network has an impact on its ability to process noisy information. Taking into account the reported variability of geometrical, electrical and receptor-dependent neuronal characteristics, I have been able to model the frequency response of a population of ORNs. I have used this model to find the key properties that govern most of the ORN population’s response, and investigated some of the possible implications of these key properties in subsequent studies of the ORN population and the OB – what we call the fuzzy concentration coding hypothesis.
Detektion av kemiska ämnen anses allmänt vara den äldsta sensoriska förmågan. De kemiska sinnena, lukt och smak, utvecklades för att upptäcka och analysera kemisk information i form av luft- eller vattenburna ämnen, för att hitta mat och partners, och för att undvika fara. Luktsystemet är organiserat efter samma principer hos nästan alla djurarter, insekter såväl som däggdjur. Troligen beror likheterna på parallell evolution – samma organisation verkar ha uppstått mer än en gång. Därför antas det ofta att luktsystemet är nära optimalt anpassat för sina arbetsuppgifter.Paradoxalt nog är luktsystemets arbetsprinciper ännu inte väl kända, även om flera banbrytande framsteg gjorts de senaste decennierna. Det mest välkända är nog upptäckten av genfamiljen av luktreceptorer, som tillkännagavs 1991 av Linda Buck och Rikard Axel. För detta och efterföljande arbete belönades de med Nobelpriset år 2004. Upptäckten har varit mycket värdefull för både experimentalister och teoretiker, och är grunden för vår nuvarande förståelse av luktsystemet. Luktsystemet har länge varit ett fokus för vetenskapligt intresse inom flera fält, experimentella såväl som teoretiska, och har ofta använts som ett modellsystem. Och ända sedan fältet beräkningsneurobiologi grundades har luktsystemet undersökts genom datormodellering. I denna avhandling presenterar jag flera ansatser till biologiskt realistiskaberäkningsmodeller av luktsystemet, med tonvikt på de tidigare delarna av ryggradsdjurens luktsystem – luktreceptorceller och luktbulben. Jag har undersökt beteendet hos enzymet CaMKII, som anses vara kritiskt viktigt för adaptation (undertryckning av ständigt närvarande luktstimuli) i luktsystemet, i en biokemisk modell. Genom att konstruera flera olika stora modeller av luktbulben har jag visat att storleken på luktbulbens cellnätverk påverkar dess förmåga att behandla brusig information. Genom att ta hänsyn till nervcellernas rapporterade variationer i geometriska, elektriska och receptor-beroende karaktärsdrag har jag lyckats modellera svarsfrekvenserna från en population av luktreceptorceller. Jag har använt denna modell för att hitta de nyckelprinciper som styr huvuddelen av luktreceptorneuron-populationens svar, ochundersökt några av de tänkbara konsekvenserna av dessa nyckelprinciper i efterföljande stu
Trita-CSC-A Tofigh Ali 1977- , KTH, Beräkningsbiologi, CB; Tofigh Ali 1977-, KTH, Cyber Biology, CB
06/2009
Dissertation
Härtill 4 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2009
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.
QC 20100812
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.
QC 20100812
Härtill 4 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2009
Svedbergssalen, Albanova, Roslagstullsbacken 21, Stockholm
Trita-CSC-A Hjorth Johannes 1978- , KTH, Beräkningsbiologi, CB; Hjorth Johannes 1978-, KTH, Cyber Biology, CB
06/2009
Dissertation
QC 20100720
Härtill 5 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2009
Svedbergssalen (FD5), Roslagstullsbacken 21, Alba Nova
Large parts of the cortex and the thalamus ...project into the striatum,which serves as the input stage of the basal ganglia. Information isintegrated in the striatal neural network and then passed on, via themedium spiny (MS) projection neurons, to the output stages of thebasal ganglia. In addition to the MS neurons there are also severaltypes of interneurons in the striatum, such as the fast spiking (FS)interneurons. I focused my research on the FS neurons, which formstrong inhibitory synapses onto the MS neurons. These striatal FSneurons are sparsely connected by electrical synapses (gap junctions),which are commonly presumed to synchronise their activity.Computational modelling with the GENESIS simulator was used toinvestigate the effect of gap junctions on a network of synapticallydriven striatal FS neurons. The simulations predicted a reduction infiring frequency dependent on the correlation between synaptic inputsto the neighbouring neurons, but only a slight synchronisation. Thegap junction effects on modelled FS neurons showing sub-thresholdoscillations and stuttering behaviour confirm these results andfurther indicate that hyperpolarising inputs might regulate the onsetof stuttering.The interactions between MS and FS neurons were investigated byincluding a computer model of the MS neuron. The hypothesis was thatdistal GABAergic input would lower the amplitude of back propagatingaction potentials, thereby reducing the calcium influx in thedendrites. The model verified this and further predicted that proximalGABAergic input controls spike timing, but not the amplitude ofdendritic calcium influx after initiation.Connecting models of neurons written in different simulators intonetworks raised technical problems which were resolved by integratingthe simulators within the MUSIC framework. This thesis discusses theissues encountered by using this implementation and gives instructionsfor modifying MOOSE scripts to use MUSIC and provides guidelines forachieving compatibility between MUSIC and other simulators.This work sheds light on the interactions between striatal FS and MSneurons. The quantitative results presented could be used to developa large scale striatal network model in the future, which would beapplicable to both the healthy and pathological striatum.
Large parts of the cortex and the thalamus project into the striatum,which serves as the input stage of the basal ganglia. Information isintegrated in the striatal neural network and then passed on, via themedium spiny (MS) projection neurons, to the output stages of thebasal ganglia. In addition to the MS neurons there are also severaltypes of interneurons in the striatum, such as the fast spiking (FS)interneurons. I focused my research on the FS neurons, which formstrong inhibitory synapses onto the MS neurons. These striatal FSneurons are sparsely connected by electrical synapses (gap junctions),which are commonly presumed to synchronise their activity.Computational modelling with the GENESIS simulator was used toinvestigate the effect of gap junctions on a network of synapticallydriven striatal FS neurons. The simulations predicted a reduction infiring frequency dependent on the correlation between synaptic inputsto the neighbouring neurons, but only a slight synchronisation. Thegap junction effects on modelled FS neurons showing sub-thresholdoscillations and stuttering behaviour confirm these results andfurther indicate that hyperpolarising inputs might regulate the onsetof stuttering.The interactions between MS and FS neurons were investigated byincluding a computer model of the MS neuron. The hypothesis was thatdistal GABAergic input would lower the amplitude of back propagatingaction potentials, thereby reducing the calcium influx in thedendrites. The model verified this and further predicted that proximalGABAergic input controls spike timing, but not the amplitude ofdendritic calcium influx after initiation.Connecting models of neurons written in different simulators intonetworks raised technical problems which were resolved by integratingthe simulators within the MUSIC framework. This thesis discusses theissues encountered by using this implementation and gives instructionsfor modifying MOOSE scripts to use MUSIC and provides guidelines forachieving compatibility between MUSIC and other simulators.This work sheds light on the interactions between striatal FS and MSneurons. The quantitative results presented could be used to developa large scale striatal network model in the future, which would beapplicable to both the healthy and pathological striatum.
QC 20100720
Härtill 5 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2009
Svedbergssalen (FD5), Roslagstullsbacken 21, Alba Nova
Phylogenomics can be regarded as evolution and genomics in co-operation. Various kinds of evolutionary studies, gene family analysis among them, demand access to genome-scale datasets. But it is also ...clear that many genomics studies, such as assignment of gene function, are much improved by evolutionary analysis. The work leading to this thesis is a contribution to the phylogenomics field. We have used phylogenetic relationships between species in genome-scale searches for two intriguing genomic features, namely and A-to-I RNA editing. In the first case we used pairwise species comparisons, specifically human-mouse and human-chimpanzee, to infer existence of functional mammalian pseudogenes. In the second case we profited upon later years' rapid growth of the number of sequenced genomes, and used 17-species multiple sequence alignments. In both these studies we have used non-genomic data, gene expression data and synteny relations among these, to verify predictions. In the A-to-I editing project we used 454 sequencing for experimental verification.
We have further contributed a maximum a posteriori (MAP) method for fast and accurate dating analysis of speciations and other evolutionary events. This work follows recent years' trend of leaving the strict molecular clock when performing phylogenetic inference. We discretised the time interval from the leaves to the root in the tree, and used a dynamic programming (DP) algorithm to optimally factorise branch lengths into substitution rates and divergence times. We analysed two biological datasets and compared our results with recent MCMC-based methodologies. The dating point estimates that our method delivers were found to be of high quality while the gain in speed was dramatic.
Finally we applied the DP strategy in a new setting. This time we used a grid laid out on a species tree instead of on an interval. The discretisation gives together with speciation times a common timeframe for a gene tree and the corresponding species tree. This is the key to integration of the sequence evolution process and the gene evolution process. Out of several potential application areas we chose gene tree reconstruction. We performed genome-wide analysis of yeast gene families and found that our methodology performs very well.
QC 20100923
Härtill 4 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2008
degree of Doctor in Technology
Teknologie doktorsexamen
FD05, Albanova, Roslagstullsbacken 21, Stockholm
QC 20100923
Härtill 4 uppsatser
Diss. (sammanfattning) Stockholm : Kungliga Tekniska högskolan, 2008
Teknologie doktorsexamen
FD05, Albanova, Roslagstullsbacken 21, Stockholm
Phylogenomics can be regarded as evolution and genomics in co-operation. Various kinds of evolutionary studies, gene family analysis among them, demand access to genome-scale datasets. But it is also clear that many genomics studies, such as assignment of gene function, are much improved by evolutionary analysis. The work leading to this thesis is a contribution to the phylogenomics field. We have used phylogenetic relationships between species in genome-scale searches for two intriguing genomic features, namely and A-to-I RNA editing. In the first case we used pairwise species comparisons, specifically human-mouse and human-chimpanzee, to infer existence of functional mammalian pseudogenes. In the second case we profited upon later years' rapid growth of the number of sequenced genomes, and used 17-species multiple sequence alignments. In both these studies we have used non-genomic data, gene expression data and synteny relations among these, to verify predictions. In the A-to-I editing project we used 454 sequencing for experimental verification.
We have further contributed a maximum a posteriori (MAP) method for fast and accurate dating analysis of speciations and other evolutionary events. This work follows recent years' trend of leaving the strict molecular clock when performing phylogenetic inference. We discretised the time interval from the leaves to the root in the tree, and used a dynamic programming (DP) algorithm to optimally factorise branch lengths into substitution rates and divergence times. We analysed two biological datasets and compared our results with recent MCMC-based methodologies. The dating point estimates that our method delivers were found to be of high quality while the gain in speed was dramatic.
Finally we applied the DP strategy in a new setting. This time we used a grid laid out on a species tree instead of on an interval. The discretisation gives together with speciation times a common timeframe for a gene tree and the corresponding species tree. This is the key to integration of the sequence evolution process and the gene evolution process. Out of several potential application areas we chose gene tree reconstruction. We performed genome-wide analysis of yeast gene families and found that our methodology performs very well.
degree of Doctor in Technology
This paper describes a generalized axiomatic scale-space theory that makes it possible to derive the notions of linear scale-space, affine Gaussian scale-space and linear spatio-temporal scale-space ...using a similar set of assumptions (scale-space axioms). The notion of non-enhancement of local extrema is generalized from previous application over discrete and rotationally symmetric kernels to continuous and more general non-isotropic kernels over both spatial and spatio-temporal image domains. It is shown how a complete classification can be given of the linear (Gaussian) scale-space concepts that satisfy these conditions on isotropic spatial, non-isotropic spatial and spatio-temporal domains, which results in a general taxonomy of Gaussian scale-spaces for continuous image data. The resulting theory allows filter shapes to be tuned from specific context information and provides a theoretical foundation for the recently exploited mechanisms of shape adaptation and velocity adaptation, with highly useful applications in computer vision. It is also shown how time-causal spatio-temporal scale-spaces can be derived from similar assumptions. The mathematical structure of these scale-spaces is analyzed in detail concerning transformation properties over space and time, the temporal cascade structure they satisfy over time as well as properties of the resulting multi-scale spatio-temporal derivative operators. It is also shown how temporal derivatives with respect to transformed time can be defined, leading to the formulation of a novel analogue of scale normalized derivatives for time-causal scale-spaces. The kernels generated from these two types of theories have interesting relations to biological vision. We show how filter kernels generated from the Gaussian spatio-temporal scale-space as well as the time-causal spatio-temporal scale-space relate to spatio-temporal receptive field profiles registered from mammalian vision. Specifically, we show that there are close analogies to space-time separable cells in the LGN as well as to both space-time separable and non-separable cells in the striate cortex. We do also present a set of plausible models for complex cells using extended quasi-quadrature measures expressed in terms of scale normalized spatio-temporal derivatives. The theories presented as well as their relations to biological vision show that it is possible to describe a general set of Gaussian and/or time-causal scale-spaces using a unified framework, which generalizes and complements previously presented scale-space formulations in this area.
QC 20110913
Published
This paper describes a generalized axiomatic scale-space theory that makes it possible to derive the notions of linear scale-space, affine Gaussian scale-space and linear spatio-temporal scale-space using a similar set of assumptions (scale-space axioms). The notion of non-enhancement of local extrema is generalized from previous application over discrete and rotationally symmetric kernels to continuous and more general non-isotropic kernels over both spatial and spatio-temporal image domains. It is shown how a complete classification can be given of the linear (Gaussian) scale-space concepts that satisfy these conditions on isotropic spatial, non-isotropic spatial and spatio-temporal domains, which results in a general taxonomy of Gaussian scale-spaces for continuous image data. The resulting theory allows filter shapes to be tuned from specific context information and provides a theoretical foundation for the recently exploited mechanisms of shape adaptation and velocity adaptation, with highly useful applications in computer vision. It is also shown how time-causal spatio-temporal scale-spaces can be derived from similar assumptions. The mathematical structure of these scale-spaces is analyzed in detail concerning transformation properties over space and time, the temporal cascade structure they satisfy over time as well as properties of the resulting multi-scale spatio-temporal derivative operators. It is also shown how temporal derivatives with respect to transformed time can be defined, leading to the formulation of a novel analogue of scale normalized derivatives for time-causal scale-spaces. The kernels generated from these two types of theories have interesting relations to biological vision. We show how filter kernels generated from the Gaussian spatio-temporal scale-space as well as the time-causal spatio-temporal scale-space relate to spatio-temporal receptive field profiles registered from mammalian vision. Specifically, we show that there are close analogies to space-time separable cells in the LGN as well as to both space-time separable and non-separable cells in the striate cortex. We do also present a set of plausible models for complex cells using extended quasi-quadrature measures expressed in terms of scale normalized spatio-temporal derivatives. The theories presented as well as their relations to biological vision show that it is possible to describe a general set of Gaussian and/or time-causal scale-spaces using a unified framework, which generalizes and complements previously presented scale-space formulations in this area.
QC 20110913
Published
