Comparative genomics: multiple genome rearrangement and efficient algorithm development

Multiple genome rearrangement by signed reversal is discussed: For a collection of genomes represented by signed permutations, reconstruct their evolutionary history by using signed reversals, i.e. find a bifurcating tree where sampled genomes are assigned to leaf nodes and ancestral genomes (i.e. signed permutations) are hypothesized at internal nodes such that the total reversal distance summed over all edges of the tree is minimized. It is equivalent to finding an optimal Steiner tree that connects the given genomes by signed reversal paths. The key for the problem is to reconstruct all optimal Steiner nodes/ancestral genomes.;The problem is NP-hard and can only be solved by efficient approximation algorithms. Various algorithms/programs have been designed to solve the problem, such as BPAnalysis, GRAPPA, grid search algorithm, MGR greedy split algorithm (Chapter 1). However, they may have expensive computational costs or low inference accuracy. In this thesis, several new algorithms are developed, including nearest path search algorithm (Chapter 2), neighbor-perturbing algorithm (Chapter 3), branch-and-bound algorithm (Chapter 3), perturbing-improving algorithm (Chapter 4), partitioning algorithm (Chapter 5), etc. With theoretical proofs, computer simulations, and biological applications, these algorithms are shown to be 2-approximation algorithms and more efficient than the existing algorithms

Approximating the double-cut-and-join distance between unsigned genomes

In this paper we study the problem of sorting unsigned genomes by double-cut-and-join operations, where genomes allow a mix of linear and circular chromosomes to be present. First, we formulate an equivalent optimization problem, called maximum cycle/path decomposition, which is aimed at finding a largest collection of edge-disjoint cycles/AA-paths/AB-paths in a breakpoint graph. Then, we show that the problem of finding a largest collection of edge-disjoint cycles/AA-paths/AB-paths of length no more than l can be reduced to the well-known degree-bounded k-set packing problem with k = 2l. Finally, a polynomial-time approximation algorithm for the problem of sorting unsigned genomes by double-cut-and-join operations is devised, which achieves the approximation ratio for any positive ε. For the restricted variation where each genome contains only one linear chromosome, the approximation ratio can be further improved t

Sobre modelos de rearranjo de genomas

Orientador: João MeidanisTese (doutorado) - Universidade Estadual de Campinas, Instituto de ComputaçãoResumo: Rearranjo de genomas é o nome dado a eventos onde grandes blocos de DNA trocam de posição durante o processo evolutivo. Com a crescente disponibilidade de sequências completas de DNA, a análise desse tipo de eventos pode ser uma importante ferramenta para o entendimento da genômica evolutiva. Vários modelos matemáticos de rearranjo de genomas foram propostos ao longo dos últimos vinte anos. Nesta tese, desenvolvemos dois novos modelos. O primeiro foi proposto como uma definição alternativa ao conceito de distância de breakpoint. Essa distância é uma das mais simples medidas de rearranjo, mas ainda não há um consenso quanto à sua definição para o caso de genomas multi-cromossomais. Pevzner e Tesler deram uma definição em 2003 e Tannier et al. a definiram de forma diferente em 2008. Nesta tese, nós desenvolvemos uma outra alternativa, chamada de single-cut-or-join (SCJ). Nós mostramos que, no modelo SCJ, além da distância, vários problemas clássicos de rearranjo, como a mediana de rearranjo, genome halving e pequena parcimônia são fáceis, e apresentamos algoritmos polinomiais para eles. O segundo modelo que apresentamos é o formalismo algébrico por adjacências, uma extensão do formalismo algébrico proposto por Meidanis e Dias, que permite a modelagem de cromossomos lineares. Esta era a principal limitação do formalismo original, que só tratava de cromossomos circulares. Apresentamos algoritmos polinomiais para o cálculo da distância algébrica e também para encontrar cenários de rearranjo entre dois genomas. Também mostramos como calcular a distância algébrica através do grafo de adjacências, para facilitar a comparação com outras distâncias de rearranjo. Por fim, mostramos como modelar todas as operações clássicas de rearranjo de genomas utilizando o formalismo algébricoAbstract: Genome rearrangements are events where large blocks of DNA exchange places during evolution. With the growing availability of whole genome data, the analysis of these events can be a very important and promising tool for understanding evolutionary genomics. Several mathematical models of genome rearrangement have been proposed in the last 20 years. In this thesis, we propose two new rearrangement models. The first was introduced as an alternative definition of the breakpoint distance. The breakpoint distance is one of the most straightforward genome comparison measures, but when it comes to defining it precisely for multichromosomal genomes, there is more than one way to go about it. Pevzner and Tesler gave a definition in a 2003 paper, and Tannier et al. defined it differently in 2008. In this thesis we provide yet another alternative, calling it single-cut-or-join (SCJ). We show that several genome rearrangement problems, such as genome median, genome halving and small parsimony, become easy for SCJ, and provide polynomial time algorithms for them. The second model we introduce is the Adjacency Algebraic Theory, an extension of the Algebraic Formalism proposed by Meidanis and Dias that allows the modeling of linear chromosomes, the main limitation of the original formalism, which could deal with circular chromosomes only. We believe that the algebraic formalism is an interesting alternative for solving rearrangement problems, with a different perspective that could complement the more commonly used combinatorial graph-theoretic approach. We present polynomial time algorithms to compute the algebraic distance and find rearrangement scenarios between two genomes. We show how to compute the rearrangement distance from the adjacency graph, for an easier comparison with other rearrangement distances. Finally, we show how all classic rearrangement operations can be modeled using the algebraic theoryDoutoradoCiência da ComputaçãoDoutor em Ciência da Computaçã

Exact and Approximation Algorithms for Computing Reversal Distances in Genome Rearrangement

Genome rearrangement is a research area capturing wide attention in molecular biology. The reversal distance problem is one of the most widely studied models of genome rearrangements in inferring the evolutionary relationship between two genomes at chromosome level. The problem of estimating reversal distance between two genomes is modeled as sorting by reversals. While the problem of sorting signed permutations can have polynomial time solutions, the problem of sorting unsigned permutations has been proven to be NP-hard [4]. This work introduces an exact greedy algorithm for sorting by reversals focusing on unsigned permutations. An improved method of producing cycle decompositions for a 3/2-approximation algorithm and the consideration of 3-cycles for reversal sequences are also presented in this paper

The distribution of cycles in breakpoint graphs of signed permutations

Breakpoint graphs are ubiquitous structures in the field of genome rearrangements. Their cycle decomposition has proved useful in computing and bounding many measures of (dis)similarity between genomes, and studying the distribution of those cycles is therefore critical to gaining insight on the distributions of the genomic distances that rely on it. We extend here the work initiated by Doignon and Labarre, who enumerated unsigned permutations whose breakpoint graph contains $k$ cycles, to signed permutations, and prove explicit formulas for computing the expected value and the variance of the corresponding distributions, both in the unsigned case and in the signed case. We also compare these distributions to those of several well-studied distances, emphasising the cases where approximations obtained in this way stand out. Finally, we show how our results can be used to derive simpler proofs of other previously known results