High Performance Computing for DNA Sequence Alignment and Assembly

Recent advances in DNA sequencing technology have dramatically increased the scale and scope of DNA sequencing. These data are used for a wide variety of important biological analyzes, including genome sequencing, comparative genomics, transcriptome analysis, and personalized medicine but are complicated by the volume and complexity of the data involved. Given the massive size of these datasets, computational biology must draw on the advances of high performance computing. Two fundamental computations in computational biology are read alignment and genome assembly. Read alignment maps short DNA sequences to a reference genome to discover conserved and polymorphic regions of the genome. Genome assembly computes the sequence of a genome from many short DNA sequences. Both computations benefit from recent advances in high performance computing to efficiently process the huge datasets involved, including using highly parallel graphics processing units (GPUs) as high performance desktop processors, and using the MapReduce framework coupled with cloud computing to parallelize computation to large compute grids. This dissertation demonstrates how these technologies can be used to accelerate these computations by orders of magnitude, and have the potential to make otherwise infeasible computations practical

SUFFIX TREE, MINWISE HASHING AND STREAMING ALGORITHMS FOR BIG DATA ANALYSIS IN BIOINFORMATICS

In this dissertation, we worked on several algorithmic problems in bioinformatics using mainly three approaches: (a) a streaming model, (b) sux-tree based indexing, and (c) minwise-hashing (minhash) and locality-sensitive hashing (LSH). The streaming models are useful for large data problems where a good approximation needs to be achieved with limited space usage. We developed an approximation algorithm (Kmer-Estimate) using the streaming approach to obtain a better estimation of the frequency of k-mer counts. A k-mer, a subsequence of length k, plays an important role in many bioinformatics analyses such as genome distance estimation. We also developed new methods that use sux tree, a trie data structure, for alignment-free, non-pairwise algorithms for a conserved non-coding sequence (CNS) identification problem. We provided two different algorithms: STAG-CNS to identify exact-matched CNSs and DiCE to identify CNSs with mismatches. Using our algorithms, CNSs among various grass species were identified. A different approach was employed for identification of longer CNSs ( 100 bp, mostly found in animals). In our new method (MinCNE), the minhash approach was used to estimate the Jaccard similarity. Using also LSH, k-mers extracted from genomic sequences were clustered and CNSs were identified. Another new algorithm (MinIsoClust) that also uses minhash and LSH techniques was developed for an isoform clustering problem. Isoforms are generated from the same gene but by alternative splicing. As the isoform sequences share some exons but in different combinations, regular sequencing clustering methods do not work well. Our algorithm generates clusters for isoform sequences based on their shared minhash signatures. Finally, we discuss de novo transcriptome assembly algorithms and how to improve the assembly accuracy using ensemble approaches. First, we did a comprehensive performance analysis on different transcriptome assemblers using simulated benchmark datasets. Then, we developed a new ensemble approach (Minsemble) for the de novo transcriptome assembly problem that integrates isoform-clustering using minhash technique to identify potentially correct transcripts from various de novo transcriptome assemblers. Minsemble identified more correctly assembled transcripts as well as genes compared to other de novo and ensemble methods. Adviser: Jitender S. Deogu

Approximating Properties of Data Streams

In this dissertation, we present algorithms that approximate properties in the data stream model, where elements of an underlying data set arrive sequentially, but algorithms must use space sublinear in the size of the underlying data set. We first study the problem of finding all k-periods of a length-n string S, presented as a data stream. S is said to have k-period p if its prefix of length n − p differs from its suffix of length n − p in at most k locations. We give algorithms to compute the k-periods of a string S using poly(k, log n) bits of space and we complement these results with comparable lower bounds. We then study the problem of identifying a longest substring of strings S and T of length n that forms a d-near-alignment under the edit distance, in the simultaneous streaming model. In this model, symbols of strings S and T are streamed at the same time and form a d-near-alignment if the distance between them in some given metric is at most d. We give several algorithms, including an exact one-pass algorithm that uses O(d2 + d log n) bits of space. We then consider the distinct elements and `p-heavy hitters problems in the sliding window model, where only the most recent n elements in the data stream form the underlying set. We first introduce the composable histogram, a simple twist on the exponential (Datar et al., SODA 2002) and smooth histograms (Braverman and Ostrovsky, FOCS 2007) that may be of independent interest. We then show that the composable histogram along with a careful combination of existing techniques to track either the identity or frequency of a few specific items suffices to obtain algorithms for both distinct elements and `p-heavy hitters that is nearly optimal in both n and c. Finally, we consider the problem of estimating the maximum weighted matching of a graph whose edges are revealed in a streaming fashion. We develop a reduction from the maximum weighted matching problem to the maximum cardinality matching problem that only doubles the approximation factor of a streaming algorithm developed for the maximum cardinality matching problem. As an application, we obtain an estimator for the weight of a maximum weighted matching in bounded-arboricity graphs and in particular, a (48 + )-approximation estimator for the weight of a maximum weighted matching in planar graphs

Accelerating Short Read Mapping Using A DSP Based Coprocessor

Advances in next generation sequencing technologies have allowed short reads to be generated at an increasing rate, shifting the bottleneck of the sequencing process to the short read mapping computations. High costs and extended processing times drive researchers to pursue more efficient solutions with an overall goal of a short read mapping architecture capable of processing short reads as they are generated. Digital signal processors have shown high performance capabilities while maintaining low power consumption in a wide field of applications. This thesis explores the use of a DSP accelerated exact match short read mapping algorithm, focusing on a performance metric to increase the number of mapped bases per watt-second. The design is implemented and tested for CPU and alternate coprocessor implementation comparisons to analyze the potential benefit of accelerating a memory bound application

Dynamic read mapping and online consensus calling for better variant detection

Variant detection from high-throughput sequencing data is an essential step in identification of alleles involved in complex diseases and cancer. To deal with these massive data, elaborated sequence analysis pipelines are employed. A core component of such pipelines is a read mapping module whose accuracy strongly affects the quality of resulting variant calls.We propose a dynamic read mapping approach that significantly improves read alignment accuracy. The general idea of dynamic mapping is to continuously update the reference sequence on the basis of previously computed read alignments. Even though this concept already appeared in the literature, we believe that our work provides the first comprehensive analysis of this approach.To evaluate the benefit of dynamic mapping, we developed a software pipeline (http://github.com/karel-brinda/dymas) that mimics different dynamic mapping scenarios. The pipeline was applied to compare dynamic mapping with the conventional static mapping and, on the other hand, with the so-called iterative referencing – a computationally expensive procedure computing an optimal modification of the reference that maximizes the overall quality of all alignments. We conclude that in all alternatives, dynamic mapping results in a much better accuracy than static mapping, approaching the accuracy of iterative referencing.To correct the reference sequence in the course of dynamic mapping, we developed an online consensus caller named Ococo (http://github.com/karel-brinda/ococo). Ococo is the first consensus caller capable to process input reads in the online fashion.Finally, we provide conclusions about the feasibility of dynamic mapping and discuss main obstacles that have to be overcome to implement it. We also review a wide range of possible applications of dynamic mapping with a special emphasis on variant detection