34 research outputs found

    On the Complexity of the Single Individual SNP Haplotyping Problem

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    We present several new results pertaining to haplotyping. These results concern the combinatorial problem of reconstructing haplotypes from incomplete and/or imperfectly sequenced haplotype fragments. We consider the complexity of the problems Minimum Error Correction (MEC) and Longest Haplotype Reconstruction (LHR) for different restrictions on the input data. Specifically, we look at the gapless case, where every row of the input corresponds to a gapless haplotype-fragment, and the 1-gap case, where at most one gap per fragment is allowed. We prove that MEC is APX-hard in the 1-gap case and still NP-hard in the gapless case. In addition, we question earlier claims that MEC is NP-hard even when the input matrix is restricted to being completely binary. Concerning LHR, we show that this problem is NP-hard and APX-hard in the 1-gap case (and thus also in the general case), but is polynomial time solvable in the gapless case.Comment: 26 pages. Related to the WABI2005 paper, "On the Complexity of Several Haplotyping Problems", but with more/different results. This papers has just been submitted to the IEEE/ACM Transactions on Computational Biology and Bioinformatics and we are awaiting a decision on acceptance. It differs from the mid-August version of this paper because here we prove that 1-gap LHR is APX-hard. (In the earlier version of the paper we could prove only that it was NP-hard.

    Algorithms, haplotypes and phylogenetic networks

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    Preface. Before I started my PhD in computational biology in 2005, I had never even heard of this term. Now, almost four years later, I think I have some idea of what is meant by it. One of the goals of my PhD was to explore different topics within computational biology and to see where the biggest opportunities for discrete/combinatorial mathematicians could be found. Roughly speaking, the first two years of my PhD I focussed mainly on problems related to haplotyping and genome rearrangements and the last two years on phylogenetic networks. I must say I really enjoyed learning so much about both mathematics and biology. It was especially amazing to learn how exact, theoretical mathematics can be used to solve complex, practical problems from biology. The topics I studied clearly show how extremely useful mathematics can be for biology. But I also learned that there are many more interesting topics in computational biology than the ones that I could study so far. The number of opportunities for discrete mathematicians is absolutely immense. I did not include my studies on genome rearrangements in this thesis, because my most interesting results [Hur07a; Hur07b] are not directly related to biology. This work is nevertheless interesting to mathematicians and I recommend them to read it. I can certainly conclude that also in this field there is a vast number of opportunities for mathematicians and that the topic genome rearrangements provides numerous beautiful mathematical problems. I could never have written this thesis without a great amount of help from many different people. I want to thank my supervisors Leen Stougie and Judith Keijsper for guiding me, for helping me, for correcting my mistakes, for supplying ideas and for the enjoyable time I had while working with them. I also want to thank the Dutch BSIK/BRICKS project for funding my research and Gerhard Woeginger for giving me the opportunity to work in his group and being my second promotor. I want to thank Jens Stoye and Julia Zakotnik for the work we did together and for the great time I had in Bielefeld. I want to thank Ferry Hagen and Teun Boekhout for helping me to make my work relevant for "real" biology. I also want to thank John Tromp, Rudi Cilibrasi, Cor Hurkens and all others I worked with during my PhD. I want to thank Erik de Vink and Mike Steel for reading and commenting my thesis. I want to thank my colleagues from the Combinatorial Optimisation group at the Technische Universiteit Eindhoven for the pleasant working conditions and the fun things we did besides work. I especially want to thank Matthias Mnich, not only a great colleague but also a good friend, for all his ideas, his humour and our good and fruitful cooperation. I also want to thank Steven Kelk. I must say that I was very lucky to work with Steven during my PhD. He introduced me to problems, had an enormous amount of ideas, found the critical mistakes in my proofs and made my PhD a success both in terms of results and in terms of enjoying work. Finally, I want to thank Conno Hendriksen and Bas Heideveld for assisting me during my PhD defence and I want to thank them and all my other friends and family for helping me with everything in my life but research

    A Decomposition of the Pure Parsimony Problem

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    We partially order a collection of genotypes so that we can represent the problem of inferring the least number of haplotypes in terms of substructures we call g-lattices. This representation allows us to prove that if the genotypes partition into chains with certain structure, then the NP-Hard problem can be solved efficiently. Even without the specified structure, the decomposition shows how to separate the underlying integer programming model into smaller models

    Pure Parsimony Xor Haplotyping

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    The haplotype resolution from xor-genotype data has been recently formulated as a new model for genetic studies. The xor-genotype data is a cheaply obtainable type of data distinguishing heterozygous from homozygous sites without identifying the homozygous alleles. In this paper we propose a formulation based on a well-known model used in haplotype inference: pure parsimony. We exhibit exact solutions of the problem by providing polynomial time algorithms for some restricted cases and a fixed-parameter algorithm for the general case. These results are based on some interesting combinatorial properties of a graph representation of the solutions. Furthermore, we show that the problem has a polynomial time k-approximation, where k is the maximum number of xor-genotypes containing a given SNP. Finally, we propose a heuristic and produce an experimental analysis showing that it scales to real-world large instances taken from the HapMap project

    Algorithmic approaches for the single individual haplotyping problem

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    Since its introduction in 2001, the Single Individual Haplotyping problem has received an ever-increasing attention from the scientific community. In this paper we survey, in the form of an annotated bibliography, the developments in the study of the problem from its origin until our days

    Introduction to the Minimum Rainbow Subgraph problem

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    Arisen from the Pure Parsimony Haplotyping problem in the bioinformatics, we developed the Minimum Rainbow Subgraph problem (MRS problem): Given a graph GG, whose edges are coloured with pp colours. Find a subgraph FsubseteqGF\\\\subseteq G of GG of minimum order and with pp edges such that each colour occurs exactly once. We proved that this problem is NP-hard, and even APX-hard. Furthermore, we stated upper and lower bounds on the order of such minimum rainbow subgraphs. Several polynomial-time approximation algorithms concerning their approximation ratio and complexity were discussed. Therefore, we used Greedy approaches, or introduced the local colour density lcd(T,S)\\\\lcd(T,S), giving a ratio on the number of colours and the number of vertices between two subgraphs S,TsubseteqGS,T\\\\subseteq G of GG. Also, we took a closer look at graphs corresponding to the original haplotyping problem and discussed their special structure.:Mathematics and biology - having nothing in common? I. Going for a start 1. Introducing haplotyping 2. Becoming mathematical II. The MRS problem 3. The graph theoretical point of view 3.1. The MRS problem 3.2. The MRS problem on special graph classes 4. Trying to be not that bad 4.1. Greedy approaches 4.2. The local colour density 4.3. MaxNewColour 5. What is real data telling us? And the work goes on and on Bibliograph

    Computational haplotyping : theory and practice

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    Genomics has paved a new way to comprehend life and its evolution, and also to investigate causes of diseases and their treatment. One of the important problems in genomic analyses is haplotype assembly. Constructing complete and accurate haplotypes plays an essential role in understanding population genetics and how species evolve. In this thesis, we focus on computational approaches to haplotype assembly from third generation sequencing technologies. This involves huge amounts of sequencing data, and such data contain errors due to the single molecule sequencing protocols employed. Taking advantage of combinatorial formulations helps to correct for these errors to solve the haplotyping problem. Various computational techniques such as dynamic programming, parameterized algorithms, and graph algorithms are used to solve this problem. This thesis presents several contributions concerning the area of haplotyping. First, a novel algorithm based on dynamic programming is proposed to provide approximation guarantees for phasing a single individual. Second, an integrative approach is introduced to combining multiple sequencing datasets to generating complete and accurate haplotypes. The effectiveness of this integrative approach is demonstrated on a real human genome. Third, we provide a novel efficient approach to phasing pedigrees and demonstrate its advantages in comparison to phasing a single individual. Fourth, we present a generalized graph-based framework for performing haplotype-aware de novo assembly. Specifically, this generalized framework consists of a hybrid pipeline for generating accurate and complete haplotypes from data stemming from multiple sequencing technologies, one that provides accurate reads and other that provides long reads.Die Genomik hat neue Wege eröffnet, die es ermöglichen, die Evolution lebendiger Organismen zu verstehen, sowie die Ursachen zahlreicher Krankheiten zu erforschen und neue Therapien zu entwickeln. Ein wichtiges Problem ist die Assemblierung der Haplotypen eines Individuums. Diese Rekonstruktion von Haplotypen spielt eine zentrale Rolle für das Verständnis der Populationsgenetik und der Evolution einer Spezies. In der vorliegenden Arbeit werden Algorithmen zur Assemblierung von Haplotypen vorgestellt, die auf Sequenzierdaten der dritten Generation basieren. Dies erfordert große Mengen an Daten, welche wiederum Fehler enthalten, die die zugrunde liegenden Sequenzierprotokolle hervorbringen. Durch kombinatorische Formulierungen des Problems ist die Rekonstruktion von Haplotypen dennoch möglich, da Fehler erfolgreich korrigiert werden können. Verschiedene informatische Methoden, wie dynamische Programmierung, parametrisierte Algorithmen und Graph Algorithmen können verwendet werden, um dieses Problem zu lösen. Die vorliegende Arbeit stellt mehrere Lösungsansätze für die Rekonstruktion von Haplotypen vor. Als erstes wird ein neuartiger Algorithmus vorgestellt, der basierend auf dem Prinzip der dynamischen Programmierung Approximationsgarantien für das Haplotyping eines einzelnen Individuums liefert. Als zweites wird ein integrativer Ansatz präsentiert, um mehrere Sequenzierdatensätze zu kombinieren und somit akkurate Haplotypen zu generieren. Die Effektivität dieser Methode wird auf einem echten, menschlichen Datensatz demonstriert. Als drittes wird ein neuer, effzienter Algorithmus beschrieben, um Haplotypen verwandter Individuen simultan zu konstruieren und die Vorteile gegenüber der Betrachtung einzelner Individuen aufgezeigt. Als viertes präsentieren wir eine Graph-basierte Methode um mittels Haplotypinformation de-novo Assemblierung durchzuführen. Dieser Methode kombiniert Daten stammend von verschiedenen Sequenziertechnologien, welche entweder genaue oder aber lange Sequenzierreads liefern

    Theory and Algorithms for the Haplotype Assembly Problem

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    On the Minimum Error Correction Problem for Haplotype Assembly in Diploid and Polyploid Genomes

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    International audienceFinding the global minimum energy conformation (GMEC) of a huge combinatorial search space is the key challenge in computational protein design (CPD) problems. Traditional algorithms lack a scalable and efficient distributed design scheme, preventing researchers from taking full advantage of current cloud infrastructures. We design cloud OSPREY (cOSPREY), an extension to a widely used protein design software OSPREY, to allow the original design framework to scale to the commercial cloud infrastructures. We propose several novel designs to integrate both algorithm and system optimizations, such as GMEC-specific pruning, state search partitioning, asynchronous algorithm state sharing, and fault tolerance. We evaluate cOSPREY on three different cloud platforms using different technologies and show that it can solve a number of large-scale protein design problems that have not been possible with previous approaches
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