SeqOthello: Querying RNA-Seq Experiments at Scale

We present SeqOthello, an ultra-fast and memory-efficient indexing structure to support arbitrary sequence query against large collections of RNA-seq experiments. It takes SeqOthello only 5 min and 19.1 GB memory to conduct a global survey of 11,658 fusion events against 10,113 TCGA Pan-Cancer RNA-seq datasets. The query recovers 92.7% of tier-1 fusions curated by TCGA Fusion Gene Database and reveals 270 novel occurrences, all of which are present as tumor-specific. By providing a reference-free, alignment-free, and parameter-free sequence search system, SeqOthello will enable large-scale integrative studies using sequence-level data, an undertaking not previously practicable for many individual labs

NOVEL COMPUTATIONAL METHODS FOR SEQUENCING DATA ANALYSIS: MAPPING, QUERY, AND CLASSIFICATION

Over the past decade, the evolution of next-generation sequencing technology has considerably advanced the genomics research. As a consequence, fast and accurate computational methods are needed for analyzing the large data in different applications. The research presented in this dissertation focuses on three areas: RNA-seq read mapping, large-scale data query, and metagenomics sequence classification. A critical step of RNA-seq data analysis is to map the RNA-seq reads onto a reference genome. This dissertation presents a novel splice alignment tool, MapSplice3. It achieves high read alignment and base mapping yields and is able to detect splice junctions, gene fusions, and circular RNAs comprehensively at the same time. Based on MapSplice3, we further extend a novel lightweight approach called iMapSplice that enables personalized mRNA transcriptional profiling. As huge amount of RNA-seq has been shared through public datasets, it provides invaluable resources for researchers to test hypotheses by reusing existing datasets. To meet the needs of efficiently querying large-scale sequencing data, a novel method, called SeqOthello, has been developed. It is able to efficiently query sequence k-mers against large-scale datasets and finally determines the existence of the given sequence. Metagenomics studies often generate tens of millions of reads to capture the presence of microbial organisms. Thus efficient and accurate algorithms are in high demand. In this dissertation, we introduce MetaOthello, a probabilistic hashing classifier for metagenomic sequences. It supports efficient query of a taxon using its k-mer signatures

ULTRA-FAST AND MEMORY-EFFICIENT LOOKUPS FOR CLOUD, NETWORKED SYSTEMS, AND MASSIVE DATA MANAGEMENT

Systems that process big data (e.g., high-traffic networks and large-scale storage) prefer data structures and algorithms with small memory and fast processing speed. Efficient and fast algorithms play an essential role in system design, despite the improvement of hardware. This dissertation is organized around a novel algorithm called Othello Hashing. Othello Hashing supports ultra-fast and memory-efficient key-value lookup, and it fits the requirements of the core algorithms of many large-scale systems and big data applications. Using Othello hashing, combined with domain expertise in cloud, computer networks, big data, and bioinformatics, I developed the following applications that resolve several major challenges in the area. Concise: Forwarding Information Base. A Forwarding Information Base is a data structure used by the data plane of a forwarding device to determine the proper forwarding actions for packets. The polymorphic property of Othello Hashing the separation of its query and control functionalities, which is a perfect match to the programmable networks such as Software Defined Networks. Using Othello Hashing, we built a fast and scalable FIB named \textit{Concise}. Extensive evaluation results on three different platforms show that Concise outperforms other FIB designs. SDLB: Cloud Load Balancer. In a cloud network, the layer-4 load balancer servers is a device that acts as a reverse proxy and distributes network or application traffic across a number of servers. We built a software load balancer with Othello Hashing techniques named SDLB. SDLB is able to accomplish two functionalities of the SDLB using one Othello query: to find the designated server for packets of ongoing sessions and to distribute new or session-free packets. MetaOthello: Taxonomic Classification of Metagenomic Sequences. Metagenomic read classification is a critical step in the identification and quantification of microbial species sampled by high-throughput sequencing. Due to the growing popularity of metagenomic data in both basic science and clinical applications, as well as the increasing volume of data being generated, efficient and accurate algorithms are in high demand. We built a system to support efficient classification of taxonomic sequences using its k-mer signatures. SeqOthello: RNA-seq Sequence Search Engine. Advances in the study of functional genomics produced a vast supply of RNA-seq datasets. However, how to quickly query and extract information from sequencing resources remains a challenging problem and has been the bottleneck for the broader dissemination of sequencing efforts. The challenge resides in both the sheer volume of the data and its nature of unstructured representation. Using the Othello Hashing techniques, we built the SeqOthello sequence search engine. SeqOthello is a reference-free, alignment-free, and parameter-free sequence search system that supports arbitrary sequence query against large collections of RNA-seq experiments, which enables large-scale integrative studies using sequence-level data