AGMIAL: implementing an annotation strategy for prokaryote genomes as a distributed system

We have implemented a genome annotation system for prokaryotes called AGMIAL. Our approach embodies a number of key principles. First, expert manual annotators are seen as a critical component of the overall system; user interfaces were cyclically refined to satisfy their needs. Second, the overall process should be orchestrated in terms of a global annotation strategy; this facilitates coordination between a team of annotators and automatic data analysis. Third, the annotation strategy should allow progressive and incremental annotation from a time when only a few draft contigs are available, to when a final finished assembly is produced. The overall architecture employed is modular and extensible, being based on the W3 standard Web services framework. Specialized modules interact with two independent core modules that are used to annotate, respectively, genomic and protein sequences. AGMIAL is currently being used by several INRA laboratories to analyze genomes of bacteria relevant to the food-processing industry, and is distributed under an open source license

INTEGRATIVE ANALYSIS OF OMICS DATA IN ADULT GLIOMA AND OTHER TCGA CANCERS TO GUIDE PRECISION MEDICINE

Transcriptomic profiling and gene expression signatures have been widely applied as effective approaches for enhancing the molecular classification, diagnosis, prognosis or prediction of therapeutic response towards personalized therapy for cancer patients. Thanks to modern genome-wide profiling technology, scientists are able to build engines leveraging massive genomic variations and integrating with clinical data to identify “at risk” individuals for the sake of prevention, diagnosis and therapeutic interventions. In my graduate work for my Ph.D. thesis, I have investigated genomic sequencing data mining to comprehensively characterise molecular classifications and aberrant genomic events associated with clinical prognosis and treatment response, through applying high-dimensional omics genomic data to promote the understanding of gene signatures and somatic molecular alterations contributing to cancer progression and clinical outcomes. Following this motivation, my dissertation has been focused on the following three topics in translational genomics. 1) Characterization of transcriptomic plasticity and its association with the tumor microenvironment in glioblastoma (GBM). I have integrated transcriptomic, genomic, protein and clinical data to increase the accuracy of GBM classification, and identify the association between the GBM mesenchymal subtype and reduced tumorpurity, accompanied with increased presence of tumor-associated microglia. Then I have tackled the sole source of microglial as intrinsic tumor bulk but not their corresponding neurosphere cells through both transcriptional and protein level analysis using a panel of sphere-forming glioma cultures and their parent GBM samples.FurthermoreI have demonstrated my hypothesis through longitudinal analysis of paired primary and recurrent GBM samples that the phenotypic alterations of GBM subtypes are not due to intrinsic proneural-to-mesenchymal transition in tumor cells, rather it is intertwined with increased level of microglia upon disease recurrence. Collectively I have elucidated the critical role of tumor microenvironment (Microglia and macrophages from central nervous system) contributing to the intra-tumor heterogeneity and accurate classification of GBM patients based on transcriptomic profiling, which will not only significantly impact on clinical perspective but also pave the way for preclinical cancer research. 2) Identification of prognostic gene signatures that stratify adult diffuse glioma patientsharboring1p/19q co-deletions. I have compared multiple statistical methods and derived a gene signature significantly associated with survival by applying a machine learning algorithm. Then I have identified inflammatory response and acetylation activity that associated with malignant progression of 1p/19q co-deleted glioma. In addition, I showed this signature translates to other types of adult diffuse glioma, suggesting its universality in the pathobiology of other subset gliomas. My efforts on integrative data analysis of this highly curated data set usingoptimizedstatistical models will reflect the pending update to WHO classification system oftumorsin the central nervous system (CNS). 3) Comprehensive characterization of somatic fusion transcripts in Pan-Cancers. I have identified a panel of novel fusion transcripts across all of TCGA cancer types through transcriptomic profiling. Then I have predicted fusion proteins with kinase activity and hub function of pathway network based on the annotation of genetically mobile domains and functional domain architectures. I have evaluated a panel of in -frame gene fusions as potential driver mutations based on network fusion centrality hypothesis. I have also characterised the emerging complexity of genetic architecture in fusion transcripts through integrating genomic structure and somatic variants and delineating the distinct genomic patterns of fusion events across different cancer types. Overall my exploration of the pathogenetic impact and clinical relevance of candidate gene fusions have provided fundamental insights into the management of a subset of cancer patients by predicting the oncogenic signalling and specific drug targets encoded by these fusion genes. Taken together, the translational genomic research I have conducted during my Ph.D. study will shed new light on precision medicine and contribute to the cancer research community. The novel classification concept, gene signature and fusion transcripts I have identified will address several hotly debated issues in translational genomics, such as complex interactions between tumor bulks and their adjacent microenvironments, prognostic markers for clinical diagnostics and personalized therapy, distinct patterns of genomic structure alterations and oncogenic events in different cancer types, therefore facilitating our understanding of genomic alterations and moving us towards the development of precision medicine

GeneNarrator: Mining the Literaturome for Relations Among Genes

The rapid development of microarray and other genomic technologies now enables biologists to monitor the expression of hundreds, even thousands of genes in a single experiment. Interpreting the biological meaning of the expression patterns still relies largely on biologist\u27s domain knowledge, as well as on information collected from the literature and various public databases. Yet individual experts’ domain knowledge is insufficient for large data sets, and collecting and analyzing this information manually from the literature and/or public databases is tedious and time-consuming. Computer-aided functional analysis tools are therefore highly desirable. We describe the architecture of GeneNarrator, a text mining system for functional analysis of microarray data. This system’s primary purpose is to test the feasibility of a more general system architecture based on a two-stage clustering strategy that is explained in detail. Given a list of genes, GeneNarrator collects abstracts about them from PubMed, then clusters the abstracts into functional topics in a first clustering stage. In the second clustering stage, the genes are clustered into groups based on similarities in their distributions of occurrence across topics. This novel two-stage architecture, the primary contribution of this project, has benefits not easily provided by onestage clustering

PrivGenDB: Efficient and privacy-preserving query executions over encrypted SNP-Phenotype database

Privacy and security issues limit the query executions over genomics datasets, notably single nucleotide polymorphisms (SNPs), raised by the sensitivity of this type of data. Therefore, it is important to ensure that executing queries on these datasets do not reveal sensitive information, such as the identity of the individuals and their genetic traits, to a data server. In this paper, we propose and present a novel model, we call PrivGenDB, to ensure the confidentiality of SNP-phenotype data while executing queries. The confidentiality in PrivGenDB is enabled by its system architecture and the search functionality provided by searchable symmetric encryption (SSE). To the best of our knowledge, PrivGenDB construction is the first SSE-based approach ensuring the confidentiality of SNP-phenotype data as the current SSE-based approaches for genomic data are limited only to substring search and range queries on a sequence of genomic data. Besides, a new data encoding mechanism is proposed and incorporated in the PrivGenDB model. This enables PrivGenDB to handle the dataset containing both genotype and phenotype and also support storing and managing other metadata, like gender and ethnicity, privately. Furthermore, different queries, namely Count, Boolean, Negation and k′-out-of-k match queries used for genomic data analysis, are supported and executed by PrivGenDB. The execution of these queries on genomic data in PrivGenDB is efficient and scalable for biomedical research and services. These are demonstrated by our analytical and empirical analysis presented in this paper. Specifically, our empirical studies on a dataset with 5000 entries (records) containing 1000 SNPs demonstrate that a count/Boolean query and a k′-out-of-k match query over 40 SNPs take approximately 4.3s and 86.4μs, respectively, outperforming the existing schemes

The Genomic HyperBrowser: inferential genomics at the sequence level

The immense increase in the generation of genomic scale data poses an unmet analytical challenge, due to a lack of established methodology with the required flexibility and power. We propose a first principled approach to statistical analysis of sequence-level genomic information. We provide a growing collection of generic biological investigations that query pairwise relations between tracks, represented as mathematical objects, along the genome. The Genomic HyperBrowser implements the approach and is available at http://hyperbrowser.uio.no

High-performance integrated virtual environment (HIVE) tools and applications for big data analysis

The High-performance Integrated Virtual Environment (HIVE) is a high-throughput cloud-based infrastructure developed for the storage and analysis of genomic and associated biological data. HIVE consists of a web-accessible interface for authorized users to deposit, retrieve, share, annotate, compute and visualize Next-generation Sequencing (NGS) data in a scalable and highly efficient fashion. The platform contains a distributed storage library and a distributed computational powerhouse linked seamlessly. Resources available through the interface include algorithms, tools and applications developed exclusively for the HIVE platform, as well as commonly used external tools adapted to operate within the parallel architecture of the system. HIVE is composed of a flexible infrastructure, which allows for simple implementation of new algorithms and tools. Currently, available HIVE tools include sequence alignment and nucleotide variation profiling tools, metagenomic analyzers, phylogenetic tree-building tools using NGS data, clone discovery algorithms, and recombination analysis algorithms. In addition to tools, HIVE also provides knowledgebases that can be used in conjunction with the tools for NGS sequence and metadata analysis