METHODS FOR HIGH-THROUGHPUT COMPARATIVE GENOMICS AND DISTRIBUTED SEQUENCE ANALYSIS

High-throughput sequencing has accelerated applications of genomics throughout the world. The increased production and decentralization of sequencing has also created bottlenecks in computational analysis. In this dissertation, I provide novel computational methods to improve analysis throughput in three areas: whole genome multiple alignment, pan-genome annotation, and bioinformatics workflows. To aid in the study of populations, tools are needed that can quickly compare multiple genome sequences, millions of nucleotides in length. I present a new multiple alignment tool for whole genomes, named Mugsy, that implements a novel method for identifying syntenic regions. Mugsy is computationally efficient, does not require a reference genome, and is robust in identifying a rich complement of genetic variation including duplications, rearrangements, and large-scale gain and loss of sequence in mixtures of draft and completed genome data. Mugsy is evaluated on the alignment of several dozen bacterial chromosomes on a single computer and was the fastest program evaluated for the alignment of assembled human chromosome sequences from four individuals. A distributed version of the algorithm is also described and provides increased processing throughput using multiple CPUs. Numerous individual genomes are sequenced to study diversity, evolution and classify pan-genomes. Pan-genome annotations contain inconsistencies and errors that hinder comparative analysis, even within a single species. I introduce a new tool, Mugsy-Annotator, that identifies orthologs and anomalous gene structure across a pan-genome using whole genome multiple alignments. Identified anomalies include inconsistently located translation initiation sites and disrupted genes due to draft genome sequencing or pseudogenes. An evaluation of pan-genomes indicates that such anomalies are common and alternative annotations suggested by the tool can improve annotation consistency and quality. Finally, I describe the Cloud Virtual Resource, CloVR, a desktop application for automated sequence analysis that improves usability and accessibility of bioinformatics software and cloud computing resources. CloVR is installed on a personal computer as a virtual machine and requires minimal installation, addressing challenges in deploying bioinformatics workflows. CloVR also seamlessly accesses remote cloud computing resources for improved processing throughput. In a case study, I demonstrate the portability and scalability of CloVR and evaluate the costs and resources for microbial sequence analysis

Design as Code: Facilitating Collaboration between Usability and Security Engineers using CAIRIS

Designing usable and secure software is hard with- out tool-support. Given the importance of requirements, CAIRIS was designed to illustrate the form tool-support for specifying usable and secure systems might take. While CAIRIS supports a broad range of security and usability engineering activities, its architecture needs to evolve to meet the workflows of these stakeholders. To this end, this paper illustrates how CAIRIS and its models act as a vehicle for collaboration between usability and security engineers. We describe how the modified architecture of CAIRIS facilitates this collaboration, and illustrate the tool using three usage scenarios

Runtime Adaptation of Scientific Service Workflows

Software landscapes are rather subject to change than being complete after having been built. Changes may be caused by a modified customer behavior, the shift to new hardware resources, or otherwise changed requirements. In such situations, several challenges arise. New architectural models have to be designed and implemented, existing software has to be integrated, and, finally, the new software has to be deployed, monitored, and, where appropriate, optimized during runtime under realistic usage scenarios. All of these situations often demand manual intervention, which causes them to be error-prone. This thesis addresses these types of runtime adaptation. Based on service-oriented architectures, an environment is developed that enables the integration of existing software (i.e., the wrapping of legacy software as web services). A workflow modeling tool that aims at an easy-to-use approach by separating the role of the workflow expert and the role of the domain expert. After the development of workflows, tools that observe the executing infrastructure and perform automatic scale-in and scale-out operations are presented. Infrastructure-as-a-Service providers are used to scale the infrastructure in a transparent and cost-efficient way. The deployment of necessary middleware tools is automatically done. The use of a distributed infrastructure can lead to communication problems. In order to keep workflows robust, these exceptional cases need to treated. But, in this way, the process logic of a workflow gets mixed up and bloated with infrastructural details, which yields an increase in its complexity. In this work, a module is presented that can deal automatically with infrastructural faults and that thereby allows to keep the separation of these two layers. When services or their components are hosted in a distributed environment, some requirements need to be addressed at each service separately. Although techniques as object-oriented programming or the usage of design patterns like the interceptor pattern ease the adaptation of service behavior or structures. Still, these methods require to modify the configuration or the implementation of each individual service. On the other side, aspect-oriented programming allows to weave functionality into existing code even without having its source. Since the functionality needs to be woven into the code, it depends on the specific implementation. In a service-oriented architecture, where the implementation of a service is unknown, this approach clearly has its limitations. The request/response aspects presented in this thesis overcome this obstacle and provide a SOA-compliant and new methods to weave functionality into the communication layer of web services. The main contributions of this thesis are the following: Shifting towards a service-oriented architecture: The generic and extensible Legacy Code Description Language and the corresponding framework allow to wrap existing software, e.g., as web services, which afterwards can be composed into a workflow by SimpleBPEL without overburdening the domain expert with technical details that are indeed handled by a workflow expert. Runtime adaption: Based on the standardized Business Process Execution Language an automatic scheduling approach is presented that monitors all used resources and is able to automatically provision new machines in case a scale-out becomes necessary. If the resource's load drops, e.g., because of less workflow executions, a scale-in is also automatically performed. The scheduling algorithm takes the data transfer between the services into account in order to prevent scheduling allocations that eventually increase the workflow's makespan due to unnecessary or disadvantageous data transfers. Furthermore, a multi-objective scheduling algorithm that is based on a genetic algorithm is able to additionally consider cost, in a way that a user can define her own preferences rising from optimized execution times of a workflow and minimized costs. Possible communication errors are automatically detected and, according to certain constraints, corrected. Adaptation of communication: The presented request/response aspects allow to weave functionality into the communication of web services. By defining a pointcut language that only relies on the exchanged documents, the implementation of services must neither be known nor be available. The weaving process itself is modeled using web services. In this way, the concept of request/response aspects is naturally embedded into a service-oriented architecture