Models and Algorithms for Sorting Permutations with Tandem Duplication and Random Loss

A central topic of evolutionary biology is the inference of phylogeny, i. e., the evolutionary history of species. A powerful tool for the inference of such phylogenetic relationships is the arrangement of the genes in mitochondrial genomes. The rationale is that these gene arrangements are subject to different types of mutations in the course of evolution. Hence, a high similarity in the gene arrangement between two species indicates a close evolutionary relation. Metazoan mitochondrial gene arrangements are particularly well suited for such phylogenetic studies as they are available for a wide range of species, their gene content is almost invariant, and usually free of duplicates. With these properties gene arrangements of mitochondrial genomes are modeled by permutations in which each element represents a gene, i. e., a specific genetic sequence. The mutations that shape the gene arrangement of genomes are then represented by operations that rearrange elements in permutations, so-called genome rearrangements, and thereby bridge the gap between evolutionary biology and optimization. Many problems of phylogeny inference can be formulated as challenging combinatorial optimization problems which makes this research area especially interesting for computer scientists. The most prominent examples of such optimization problems are the sorting problem and the distance problem. While the sorting problem requires a minimum length sequence of rearrangements that transforms one given permutation into another given permutation, i. e., it aims for a hypothetical scenario of gene order evolution, the distance problem intends to determine only the length of such a sequence. This minimum length is called distance and used as a (dis)similarity measure quantifying the evolutionary relatedness. Most evolutionary changes occurring in gene arrangements of mitochondrial genomes can be explained by the tandem duplication random loss (TDRL) genome rearrangement model. A TDRL consists of a duplication of a consecutive set of genes in tandem followed by a random loss of one copy of each duplicated gene. In spite of the importance of the TDRL genome rearrangement in mitochondrial evolution, its combinatorial properties have rarely been studied. In addition, models of genome rearrangements which include all types of rearrangement that are relevant for mitochondrial genomes, i. e., inversions, transpositions, inverse transpositions, and TDRLs, while admitting computational tractability are rare. Nevertheless, especially for metazoan gene arrangements the TDRL rearrangement should be considered for the reconstruction of phylogeny. Realizing that a better understanding of the TDRL model is indispensable for the study of mitochondrial gene arrangements, the central theme of this thesis is to broaden the horizon of TDRL genome rearrangements with respect to mitochondrial genome evolution. For this purpose, this thesis provides combinatorial properties of the TDRL model and its variants as well as efficient methods for a plausible reconstruction of rearrangement scenarios between gene arrangements. The methods that are proposed consider all types of genome rearrangements that predominately occur during mitochondrial evolution. More precisely, the main points contained in this thesis are as follows: The distance problem and the sorting problem for the TDRL model are further examined in respect to circular permutations, a formal concept that reflects the circular structure of mitochondrial genomes. As a result, a closed formula for the distance is provided. Recently, evidence for a variant of the TDRL rearrangement model in which the duplicated set of genes is additionally inverted have been found. Initiating the algorithmic study of this new rearrangement model on a certain type of permutations, a closed formula solving the distance problem is proposed as well as a quasilinear time algorithm that solves the corresponding sorting problem. The assumption that only one type of genome rearrangement has occurred during the evolution of certain gene arrangements is most likely unrealistic, e. g., at least three types of rearrangements on top of the TDRL rearrangement have to be considered for the evolution metazoan mitochondrial genomes. Therefore, three different biologically motivated constraints are taken into account in this thesis in order to produce plausible evolutionary rearrangement scenarios. The first constraint is extending the considered set of genome rearrangements to the model that covers all four common types of mitochondrial genome rearrangements. For this 4-type model a sharp lower bound and several close additive upper bounds on the distance are developed. As a byproduct, a polynomial-time approximation algorithm for the corresponding sorting problem is provided that guarantees the computation of pairwise rearrangement scenarios that deviate from a minimum length scenario by at most two rearrangement operations. The second biologically motivated constraint is the relative frequency of the different types of rearrangements occurring during the evolution. The frequency is modeled by employing a weighting scheme on the 4-type model in which every rearrangement is weighted with respect to its type. The resulting NP-hard sorting problem is then solved by means of a polynomial size integer linear program. The third biologically motivated constraint that has been taken into account is that certain subsets of genes are often found in close proximity in the gene arrangements of many different species. This observation is reflected by demanding rearrangement scenarios to preserve certain groups of genes which are modeled by common intervals of permutations. In order to solve the sorting problem that considers all three types of biologically motivated constraints, the exact dynamic programming algorithm CREx2 is proposed. CREx2 has a linear runtime for a large class of problem instances. Otherwise, two versions of the CREx2 are provided: The first version provides exact solutions but has an exponential runtime in the worst case and the second version provides approximated solutions efficiently. CREx2 is evaluated by an empirical study for simulated artificial and real biological mitochondrial gene arrangements

Rearranjo de genomas : uma coletanea de artigos

Orientador : João MeidanisTese (doutorado) - Universidade Estadual de Campinas, Instituto de ComputaçãoResumo: Hoje em dia, estão disponíveis, publicamente, uma imensa quantidade de informações genéticas. O desafio atual da Genômica é processar estes dados de forma a obter conclusões biológicas relevantes. Uma das maneiras de estruturar estas informações é através de comparação de genomas, que busca semelhanças e diferenças entre os genomas de dois ou mais organismos. Neste contexto, a área de Rearranjo de Genomas vem recebendo bastante atenção ultimamente. Uma forma de comparar genomas é através da distância de rearranjo, determinada pelo número mínimo de eventos de rearranjo que podem explicar as diferenças entre dois genomas. Os principais estudos em distância de rearranjo envolvem eventos de reversões e transposições. A presente coletânea é composta de oito artigos, contendo vários resultados importantes sobre Rearranjo de Genomas. Estes trabalhos foram apresentados em seis conferências, sendo uma nacional e cinco internacionais. Dois destes trabalhos serão publicados em importantes revistas internacionais e outro foi incluído como um capítulo de um livro. Nossas principais contribuições podem ser divididas em dois grupos: um novo formalismo algébrico e uma série de resultados envolvendo o evento de transposição. A nova teoria algébrica relaciona a teoria de Rearranjo de Genomas com a de grupos de permutações. Nossa intenção foi estabelecer um formalismo algébrico que simplificasse a obtenção de novos resultados, até hoje, muito baseados na construção de diagramas. Estudamos o evento de transposição de várias formas. Além de apresentarmos resultados sobre a distância de transposição entre uma permutação e sua inversa, também estudamos o problema de rearranjo envolvendo transposições e reversões simultaneamente, construindo algoritmos de aproximação e estabelecendo uma conjectura sobre o diâmetro. Usamos o formalismo algébrico para mostrar que é possível determinar a distância de fusão, fissão e transposição em tempo polinomial. Este é o primeiro resultado polinomial conhecido para um problema de rearranjo envolvendo o evento de transposição. Por último, introduzimos dois novos problemas de rearranjo: o problema de distância sintênica envolvendo fusões e fissões, e o problema de transposição de prefixos. Para ambos apresentamos resultados significativos, que avançam o conhecimento na áreaAbstract: Nowadays, a huge amount of genetic information is public1y available. Genomic's current challenge is to process this information in order to obtain relevant biological conc1usions. One possible way of structuring this information is through genome comparison, where we seek similarities and differences among the genomes of two or more organisms. In this context, the area of Genome Rearrangements has received considerable attention lately. One way of comparing genomes is given by the rearrangement distance, which is determined by the minimum number of rearrangement events that explain the differences between two genomes. The main studies in rearrangement distance involve reversal and transposition events. The present collection is composed of eight artic1es, containing several important results on Genome Rearrangements. These papers were presented in six conferences, one with Brazilian scope and five with international scope. Two of these works will be published in important international journals, and one other work appeared as a book chapter. Our main contributions can be divided into two groups: a new algebraic formalism and a series of results involving the transposition event. The new algebraic theory relates the genome rearrangement theory to the theory of permutation groups. Our intention was to establish an algebraic formalism that simplifies the creation of new results, up to now excessively based on the construction of diagrams. We studied the transposition event in several ways. Besides presenting results on the transpositions distance between a permutation and its inverse, we also studied the rearrangement problem involving transpositions and reversals simultaneously, constructing approximation algorithms and proposing a conjecture on the diameter. We used the algebraic formalism to show that it is possible to determine the distance of fusion, fission, and transposition in polynomial time. This is the first polynomial time result for a rearrangement problem involving the transposition event. Finally, we introduced two now rearrangement problems: the syntenic distance problem involving fission and fusion, and the prefix transposition problem. For each one of these problems we present significant results, widening the knowledge in this areaDoutoradoDoutor em Ciência da Computaçã

Gene rearrangement analysis and ancestral order inference from chloroplast genomes with inverted repeat

Background Genome evolution is shaped not only by nucleotide substitutions, but also by structural changes including gene and genome duplications, insertions, deletions and gene order rearrangements. The most popular methods for reconstructing phylogeny from genome rearrangements include GRAPPA and MGR. However these methods are limited to cases where equal gene content or few deletions can be assumed. Since conserved duplicated regions are present in many chloroplast genomes, the inference of inverted repeats is needed in chloroplast phylogeny analysis and ancestral genome reconstruction. Results We extend GRAPPA and develop a new method GRAPPA-IR to handle chloroplast genomes. A test of GRAPPA-IR using divergent chloroplast genomes from land plants and green algae recovers the phylogeny congruent with prior studies, while analysis that do not consider IR structure fail to obtain the accepted topology. Our extensive simulation study also confirms that GRAPPA has better accuracy then the existing methods. Conclusions Tests on a biological and simulated dataset show GRAPPA-IR can accurately recover the genome phylogeny as well as ancestral gene orders. Close analysis of the ancestral genome structure suggests that genome rearrangement in chloroplasts is probably limited by inverted repeats with a conserved core region. In addition, the boundaries of inverted repeats are hot spots for gene duplications or deletions. The new GRAPPA-IR is available from http://phylo.cse.sc.ed

Combinatorial Optimization

This report summarizes the meeting on Combinatorial Optimization where new and promising developments in the field were discussed. Th

Réarrangement de génomes par inversions et analyse de l'ensemble des solutions minimales

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

SAT and CP: Parallelisation and Applications

This thesis is considered with the parallelisation of solvers which search for either an arbitrary, or an optimum, solution to a problem stated in some formal way. We discuss the parallelisation of two solvers, and their application in three chapters.In the first chapter, we consider SAT, the decision problem of propositional logic, and algorithms for showing the satisfiability or unsatisfiability of propositional formulas. We sketch some proof-theoretic foundations which are related to the strength of different algorithmic approaches. Furthermore, we discuss details of the implementations of SAT solvers, and show how to improve upon existing sequential solvers. Lastly, we discuss the parallelisation of these solvers with a focus on clause exchange, the communication of intermediate results within a parallel solver. The second chapter is concerned with Contraint Programing (CP) with learning. Contrary to classical Constraint Programming techniques, this incorporates learning mechanisms as they are used in the field of SAT solving. We present results from parallelising CHUFFED, a learning CP solver. As this is both a kind of CP and SAT solver, it is not clear which parallelisation approaches work best here. In the final chapter, we will discuss Sorting networks, which are data oblivious sorting algorithms, i. e., the comparisons they perform do not depend on the input data. Their independence of the input data lends them to parallel implementation. We consider the question how many parallel sorting steps are needed to sort some inputs, and present both lower and upper bounds for several cases

Chronic Stress Effects on Prefrontal Cortical Structure and Function

Stressful life events have been implicated clinically in the pathogenesis of major depression, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of depression are associated with structural and functional abnormalities in the prefrontal cortex. In three parallel rodent and human neuroimaging studies, this project assessed the effects of chronic stress on prefrontal cortical structure and function and the behavioral correlates of these changes. The first study used fMRI to elucidate the precise computational contributions of frontoparietal circuitry to attentional control in human subjects, using a task that could be adapted for rats. The results confirmed that the contributions of dorsolateral frontoparietal areas to visual attentional shifts could be dissociated from the regulatory influences of more ventrolateral areas on stimulus/response mappings, in a manner consistent with studies in animal models. They also indicated that anterior cingulate and posterior parietal cortex may act in concert to detect dissociable forms of information processing conflicts and signal to dorsolateral prefrontal cortex the need for increased attentional control. Stress-induced alterations in these regions and in the connections between them may therefore contribute to attentional impairments. The second study tested this hypothesis in rats by examining whether chronic stress effects on medial prefrontal (mPFC) and orbitofrontal (OFC) dendritic morphology underlie impairments in the behaviors that they subserve. Chronic stress induced a selective impairment in attentional control and a corresponding retraction of apical dendritic arbors in mPFC. By contrast, stress did not adversely affect reversal learning or OFC dendritic arborization. These results suggest that prefrontal dendritic remodeling may underlie the attentional deficits that are symptomatic of stress-related mental illness. The third study was designed to extend these findings to human subjects, using the techniques developed in Study 1. Accordingly, chronic stress predicted selective attentional impairments and alterations in prefrontal functional coupling that were reversible after four weeks. Together, these studies outline in broad strokes a mechanistic model by which chronic stress may predispose susceptible persons to the attentional impairments that are characteristic of major depression. Future studies will assess the roles of serotonin and neurotrophins in mediating these changes