High-Performance approaches for Phylogenetic Placement, and its application to species and diversity quantification

In den letzten Jahren haben Fortschritte in der Hochdurchsatz-Genesequenzierung, in Verbindung mit dem anhaltenden exponentiellen Wachstum und der Verfügbarkeit von Rechenressourcen, zu fundamental neuen analytischen Ansätzen in der Biologie geführt. Es ist nun möglich den genetischen Inhalt ganzer Organismengemeinschaften anhand einzelner Umweltproben umfassend zu sequenzieren. Solche Methoden sind besonders für die Mikrobiologie relevant. Die Mikrobiologie war zuvor weitgehend auf die Untersuchung jener Mikroben beschränkt, welche im Labor (d.h., in vitro) kultiviert werden konnten, was jedoch lediglich einen kleinen Teil der in der Natur vorkommenden Diversität abdeckt. Im Gegensatz dazu ermöglicht die Hochdurchsatzsequenzierung nun die direkte Erfassung der genetischen Sequenzen eines Mikrobioms, wie es in seiner natürlichen Umgebung vorkommt (d.h., in situ). Ein typisches Ziel von Mikrobiomstudien besteht in der taxonomischen Klassifizierung der in einer Probe enthaltenen Sequenzen (Querysequenzen). Üblicherweise werden phylogenetische Methoden eingesetzt, um detaillierte taxonomische Beziehungen zwischen Querysequenzen und vertrauenswürdigen Referenzsequenzen, die von bereits klassifizierten Organismen stammen, zu bestimmen. Aufgrund des hohen Volumens ($10 ^ 6$ bis $10 ^ 9$) von Querysequenzen, die aus einer Mikrobiom-Probe mittels Hochdurchsatzsequenzierung generiert werden können, ist eine akkurate phylogenetische Baumrekonstruktion rechnerisch nicht mehr möglich. Darüber hinaus erzeugen derzeit üblicherweise verwendete Sequenzierungstechnologien vergleichsweise kurze Sequenzen, die ein begrenztes phylogenetisches Signal aufweisen, was zu einer Instabilität bei der Inferenz der Phylogenien aus diesen Sequenzen führt. Ein weiteres typisches Ziel von Mikrobiomstudien besteht in der Quantifizierung der Diversität innerhalb einer Probe, bzw. zwischen mehreren Proben. Auch hierfür werden üblicherweise phylogenetische Methoden verwendet. Oftmals setzen diese Methoden die Inferenz eines phylogenetischen Baumes voraus, welcher entweder alle Sequenzen, oder eine geclusterte Teilmenge dieser Sequenzen, umfasst. Wie bei der taxonomischen Identifizierung können Analysen, die auf dieser Art von Bauminferenz basieren, zu ungenauen Ergebnissen führen und/oder rechnerisch nicht durchführbar sein. Im Gegensatz zu einer umfassenden phylogenetischen Inferenz ist die phylogenetische Platzierung eine Methode, die den phylogenetischen Kontext einer Querysequenz innerhalb eines etablierten Referenzbaumes bestimmt. Dieses Verfahren betrachtet den Referenzbaum typischerweise als unveränderlich, d.h. der Referenzbaum wird vor, während oder nach der Platzierung einer Sequenz nicht geändert. Dies erlaubt die phylogenetische Platzierung einer Sequenz in linearer Zeit in Bezug auf die Größe des Referenzbaums durchzuführen. In Kombination mit taxonomischen Informationen über die Referenzsequenzen ermöglicht die phylogenetische Platzierung somit die taxonomische Identifizierung einer Sequenz. Darüber hinaus erlaubt eine phylogenetische Platzierung die Anwendung einer Vielzahl zusätzlicher Analyseverfahren, die beispielsweise die Zuordnung der Zusammensetzungen humaner Mikrobiome zu klinisch-diagnostischen Eigenschaften ermöglicht. In dieser Dissertation präsentiere ich meine Arbeit bezüglich des Entwurfs, der Implementierung, und Verbesserung von EPA-ng, einer Hochleistungsimplementierung der phylogenetischen Platzierung anhand des Maximum-Likelihood Modells. EPA-ng wurde entwickelt um auf Milliarden von Querysequenzen zu skalieren und auf Tausenden von Kernen in Systemen mit gemeinsamem und verteiltem Speicher ausgeführt zu werden. EPA-ng beschleunigt auch die Verarbeitungsgeschwindigkeit auf einzelnen Kernen um das bis zu $30$-fache, im Vergleich zu dessen direkten Konkurrenzprogrammen. Vor kurzem haben wir eine zusätzliche Methode für EPA-ng eingeführt, welche die Platzierung in wesentlich größeren Referenzbäumen ermöglicht. Hierfür verwenden wir einen aktiven Speicherverwaltungsansatz, bei dem reduzierter Speicherverbrauch gegen größere Ausführungszeiten eingetauscht wird. Zusätzlich präsentiere ich einen massiv-parallelen Ansatz um die Diversität einer Probe zu quantifizieren, welcher auf den Ergebnissen phylogenetischer Platzierungen basiert. Diese Software, genannt \toolname{SCRAPP}, kombiniert aktuelle Methoden für die Maximum-Likelihood basierte phylogenetische Inferenz mit Methoden zur Abgrenzung molekularer Spezien. Daraus resultiert eine Verteilung der Artenanzahl auf den Kanten eines Referenzbaums für eine gegebene Probe. Darüber hinaus beschreibe ich einen neuartigen Ansatz zum Clustering von Platzierungsergebnissen, anhand dessen der Benutzer den Rechenaufwand reduzieren kann

Exploring New Search Algorithms and Hardware for Phylogenetics: RAxML Meets the IBM Cell

Phylogenetic inference is considered to be one of the grand challenges in Bioinformatics due to the immense computational requirements. RAxML is currently among the fastest and most accurate programs for phylogenetic tree inference under the Maximum Likelihood (ML) criterion. First, we introduce new tree search heuristics that accelerate RAxML by a factor of 2.43 while returning equally good trees. The performance of the new search algorithm has been assessed on 18 real-world datasets comprising 148 up to 4,843 DNA sequences. We then present the implementation, optimization, and evaluation of RAxML on the IBM Cell Broadband Engine. We address the problems and provide solutions pertaining to the optimization of floating point code, control flow, communication, and scheduling of multi-level parallelism on the Cel

RAxML-Cell: Parallel Phylogenetic Tree Inference on the Cell Broadband Engine

Phylogenetic tree reconstruction is one of the grand challenge problems in Bioinformatics. The search for a best-scoring tree with 50 organisms, under a reasonable optimality criterion, creates a topological search space which is as large as the number of atoms in the universe. Computational phylogeny is challenging even for the most powerful supercomputers. It is also an ideal candidate for benchmarking emerging multiprocessor architectures, because it exhibits various levels of fine and coarse-grain parallelism. In this paper, we present the porting, optimization, and evaluation of RAxML on the Cell Broadband Engine. RAxML is a provably efficient, hill climbing algorithm for computing phylogenetic trees based on the Maximum Likelihood (ML) method. The algorithm uses an embarrassingly parallel search method, which also exhibits data-level parallelism and control parallelism in the computation of the likelihood functions. We present the optimization of one of the currently fastest tree search algorithms, on a real Cell blade prototype. We also investigate problems and present solutions pertaining to the optimization of floating point code, control flow, communication, scheduling, and multi-level parallelization on the Cell

On FPGA implementations for bioinformatics, neural prosthetics and reinforcement learning problems.

Mak Sui Tung Terrence.Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.Includes bibliographical references (leaves 132-142).Abstracts in English and Chinese.Abstract --- p.iList of Tables --- p.ivList of Figures --- p.vAcknowledgements --- p.ixChapter 1. --- Introduction --- p.1Chapter 1.1 --- Bioinformatics --- p.1Chapter 1.2 --- Neural Prosthetics --- p.4Chapter 1.3 --- Learning in Uncertainty --- p.5Chapter 1.4 --- The Field Programmable Gate Array (FPGAs) --- p.7Chapter 1.5 --- Scope of the Thesis --- p.10Chapter 2. --- A Hybrid GA-DP Approach for Searching Equivalence Sets --- p.14Chapter 2.1 --- Introduction --- p.16Chapter 2.2 --- Equivalence Set Criterion --- p.18Chapter 2.3 --- Genetic Algorithm and Dynamic Programming --- p.19Chapter 2.3.1 --- Genetic Algorithm Formulation --- p.20Chapter 2.3.2 --- Bounded Mutation --- p.21Chapter 2.3.3 --- Conditioned Crossover --- p.22Chapter 2.3.4 --- Implementation --- p.22Chapter 2.4 --- FPGAs Implementation of GA-DP --- p.24Chapter 2.4.1 --- System Overview --- p.25Chapter 2.4.2 --- Parallel Computation for Transitive Closure --- p.26Chapter 2.4.3 --- Genetic Operation Realization --- p.28Chapter 2.5 --- Discussion --- p.30Chapter 2.6 --- Limitation and Future Work --- p.33Chapter 2.7 --- Conclusion --- p.34Chapter 3. --- An FPGA-based Architecture for Maximum-Likelihood Phylogeny Evaluation --- p.35Chapter 3.1 --- Introduction --- p.36Chapter 3.2 --- Maximum-Likelihood Model --- p.39Chapter 3.3 --- Hardware Mapping for Pruning Algorithm --- p.41Chapter 3.3.1 --- Related Works --- p.41Chapter 3.3.2 --- Number Representation --- p.42Chapter 3.3.3 --- Binary Tree Representation --- p.43Chapter 3.3.4 --- Binary Tree Traversal --- p.45Chapter 3.3.5 --- Maximum-Likelihood Evaluation Algorithm --- p.46Chapter 3.4 --- System Architecture --- p.49Chapter 3.4.1 --- Transition Probability Unit --- p.50Chapter 3.4.2 --- State-Parallel Computation Unit --- p.51Chapter 3.4.3 --- Error Computation --- p.54Chapter 3.5 --- Discussion --- p.56Chapter 3.5.1 --- Hardware Resource Consumption --- p.56Chapter 3.5.2 --- Delay Evaluation --- p.57Chapter 3.6 --- Conclusion --- p.59Chapter 4. --- Field Programmable Gate Array Implementation of Neuronal Ion Channel Dynamics --- p.61Chapter 4.1 --- Introduction --- p.62Chapter 4.2 --- Background --- p.63Chapter 4.2.1 --- Analog VLSI Model for Hebbian Synapse --- p.63Chapter 4.2.2 --- A Unifying Model of Bi-directional Synaptic Plasticity --- p.64Chapter 4.2.3 --- Non-NMDA Receptor Channel Regulation --- p.65Chapter 4.3 --- FPGAs Implementation --- p.65Chapter 4.3.1 --- FPGA Design Flow --- p.65Chapter 4.3.2 --- Digital Model of NMD A and AMPA receptors --- p.65Chapter 4.3.3 --- Synapse Modification --- p.67Chapter 4.4 --- Results --- p.68Chapter 4.4.1 --- Simulation Results --- p.68Chapter 4.5 --- Discussion --- p.70Chapter 4.6 --- Conclusion --- p.71Chapter 5. --- Continuous-Time and Discrete-Time Inference Networks for Distributed Dynamic Programming --- p.72Chapter 5.1 --- Introduction --- p.74Chapter 5.2 --- Background --- p.77Chapter 5.2.1 --- Markov decision process (MDPs) --- p.78Chapter 5.2.2 --- Learning in the MDPs --- p.80Chapter 5.2.3 --- Bellman Optimal Criterion --- p.80Chapter 5.2.4 --- Value Iteration --- p.81Chapter 5.3 --- A Computational Framework for Continuous-Time Inference Network --- p.82Chapter 5.3.1 --- Binary Relation Inference Network --- p.83Chapter 5.3.2 --- Binary Relation Inference Network for MDPs --- p.85Chapter 5.3.3 --- Continuous-Time Inference Network for MDPs --- p.87Chapter 5.4 --- Convergence Consideration --- p.88Chapter 5.5 --- Numerical Simulation --- p.90Chapter 5.5.1 --- Example 1: Random Walk --- p.90Chapter 5.5.2 --- Example 2: Random Walk on a Grid --- p.94Chapter 5.5.3 --- Example 3: Stochastic Shortest Path Problem --- p.97Chapter 5.5.4 --- Relationships Between λ and γ --- p.99Chapter 5.6 --- Discrete-Time Inference Network --- p.100Chapter 5.6.1 --- Results --- p.101Chapter 5.7 --- Conclusion --- p.102Chapter 6. --- On Distributed g-Learning Network --- p.104Chapter 6.1 --- Introduction --- p.105Chapter 6.2 --- Distributed Q-Learniing Network --- p.108Chapter 6.2.1 --- Distributed Q-Learning Network --- p.109Chapter 6.2.2 --- Q-Learning Network Architecture --- p.111Chapter 6.3 --- Experimental Results --- p.114Chapter 6.3.1 --- Random Walk --- p.114Chapter 6.3.2 --- The Shortest Path Problem --- p.116Chapter 6.4 --- Discussion --- p.120Chapter 6.4.1 --- Related Work --- p.121Chapter 6.5 --- FPGAs Implementation --- p.122Chapter 6.5.1 --- Distributed Registering Approach --- p.123Chapter 6.5.2 --- Serial BRAM Storing Approach --- p.124Chapter 6.5.3 --- Comparison --- p.125Chapter 6.5.4 --- Discussion --- p.127Chapter 6.6 --- Conclusion --- p.128Chapter 7. --- Summary --- p.129Bibliography --- p.132AppendixChapter A. --- Simplified Floating-Point Arithmetic --- p.143Chapter B. --- "Logarithm, Exponential and Division Implementation" --- p.144Chapter B.1 --- Introduction --- p.144Chapter B.2 --- Approximation Scheme --- p.145Chapter B.2.1 --- Logarithm --- p.145Chapter B.2.2 --- Exponentiation --- p.147Chapter B.2.3 --- Division --- p.148Chapter C. --- Analog VLSI Implementation --- p.150Chapter C.1 --- Site Function --- p.150Chapter C.1.1 --- Multiplication Cell --- p.150Chapter C.2 --- The Unit Function --- p.153Chapter C.3 --- The Inference Network Computation --- p.154Chapter C.4 --- Layout --- p.157Chapter C.5 --- Fabrication --- p.159Chapter C.5.1 --- Testing and Characterization --- p.16

BEAGLE 3:Improved Performance, Scaling, and Usability for a High-Performance Computing Library for Statistical Phylogenetics

© 2019 The Author(s). BEAGLE is a high-performance likelihood-calculation library for phylogenetic inference. The BEAGLE library defines a simple, but flexible, application programming interface (API), and includes a collection of efficient implementations for calculation under a variety of evolutionary models on different hardware devices. The library has been integrated into recent versions of popular phylogenetics software packages including BEAST and MrBayes and has been widely used across a diverse range of evolutionary studies. Here, we present BEAGLE 3 with new parallel implementations, increased performance for challenging data sets, improved scalability, and better usability. We have added new OpenCL and central processing unit-threaded implementations to the library, allowing the effective utilization of a wider range of modern hardware. Further, we have extended the API and library to support concurrent computation of independent partial likelihood arrays, for increased performance of nucleotide-model analyses with greater flexibility of data partitioning. For better scalability and usability, we have improved how phylogenetic software packages use BEAGLE in multi-GPU (graphics processing unit) and cluster environments, and introduced an automated method to select the fastest device given the data set, evolutionary model, and hardware. For application developers who wish to integrate the library, we also have developed an online tutorial. To evaluate the effect of the improvements, we ran a variety of benchmarks on state-of-the-art hardware. For a partitioned exemplar analysis, we observe run-time performance improvements as high as 5.9-fold over our previous GPU implementation. BEAGLE 3 is free, open-source software licensed under the Lesser GPL and available at https://beagle-dev.github.io

Computational Biology and High Performance Computing 2000

Tutorial to be presented at Supercomputing 2000, Dallas TX, 6-10 November 2000.This work was supported by the Director, Office of Science, Office of Advanced Scientific computing Research, Mathematical, Information, and Computational Sciences Division of the U.S. Department of Energy under Contract No. DE-AC03-76SF0009

Computational Biology and High Performance Computing 2000

Tutorial to be presented at Supercomputing 2000, Dallas TX, 6-10 November 2000.This work was supported by the Director, Office of Science, Office of Advanced Scientific computing Research, Mathematical, Information, and Computational Sciences Division of the U.S. Department of Energy under Contract No. DE-AC03-76SF0009

Finding the Core-Genes of Chloroplasts

Due to the recent evolution of sequencing techniques, the number of available genomes is rising steadily, leading to the possibility to make large scale genomic comparison between sets of close species. An interesting question to answer is: what is the common functionality genes of a collection of species, or conversely, to determine what is specific to a given species when compared to other ones belonging in the same genus, family, etc. Investigating such problem means to find both core and pan genomes of a collection of species, \textit{i.e.}, genes in common to all the species vs. the set of all genes in all species under consideration. However, obtaining trustworthy core and pan genomes is not an easy task, leading to a large amount of computation, and requiring a rigorous methodology. Surprisingly, as far as we know, this methodology in finding core and pan genomes has not really been deeply investigated. This research work tries to fill this gap by focusing only on chloroplastic genomes, whose reasonable sizes allow a deep study. To achieve this goal, a collection of 99 chloroplasts are considered in this article. Two methodologies have been investigated, respectively based on sequence similarities and genes names taken from annotation tools. The obtained results will finally be evaluated in terms of biological relevance

Parallelization of the maximum likelihood approach to phylogenetic inference

Phylogenetic inference refers to the reconstruction of evolutionary relationships among various species, usually presented in the form of a tree. DNA sequences are most often used to determine these relationships. The results of phylogenetic inference have many important applications, including protein function determination, drug discovery, disease tracking and forensics. There are several popular computational methods used for phylogenetic inference, among them distance-based (i.e. neighbor joining), maximum parsimony, maximum likelihood, and Bayesian methods. This thesis focuses on the maximum likelihood method, which is regarded as one of the most accurate methods, with its computational demand being the main hindrance to its widespread use. Maximum likelihood is generally considered to be a heuristic method providing a statistical evaluation of the results, where potential tree topologies are judged by how well they predict the observed sequences. While there have been several previous efforts to parallelize the maximum likelihood method, sequential implementations are more widely used in the biological research community. This is due to a lack of confidence in the results produced by the more recent, parallel programs. However, because phylogenetic inference can be extremely computationally intensive, with the number of possible tree topologies growing exponentially with the number of species, parallelization is necessary to reduce the computation time to a reasonable amount. A parallel program was developed for phylogenetic inference based on the trusted algorithms of fastDNAml, a sequential program for phylogenetic inference utilizing the maximum likelihood approach. Parallelization is achieved using the popular master/workers scheme, where workers evaluate potential tree topologies in parallel. Three innovative optimizations are employed to alleviate the associated communication bottleneck encountered when using the master/workers technique with large-scale systems and problems. First, message packing reduces the number of messages sent out by the master, along with the associated overheads. Secondly, allowing workers to keep the best trees evaluated reduces the number of messages received by the master, as low-scoring results are discarded by the workers. Finally, multiple masters are utilized to parallelize the responsibilities of what is traditionally a single master process. These last two optimizations led to a dramatic improvement in performance over the unoptimized parallelization under the conditions tested. Message packing, however, demonstrated a slight reduction in performance. Although testing with large-scale systems and problems was not possible, results for all three optimizations suggested likely performance enhancement under such conditions, potentially leading to relief of the bottleneck