Interpreting Human Genetic Variation through Genomics and In Vivo Models

Improvements in genomic technology, both in the increased speed and reduced cost of sequencing, have expanded the appreciation of the abundance of human genetic variation. However the sheer amount of variation, as well as the varying type and genomic content of variation, poses a challenge in understanding the clinical consequence of a single mutation. This work uses several methodologies to interpret the observed variation in the human genome, and presents novel strategies for the prediction of allele pathogenicity.

Using the zebrafish model system as an in vivo assay of allele function, we identified a novel driver of Bardet-Biedl Syndrome (BBS) in CEP76. A combination of targeted sequencing of 785 cilia-associated genes in a cohort of BBS patients and subsequent in vivo functional assays recapitulating the human phenotype gave strong evidence for the role of CEP76 mutations in the pathology of an affected family. This portion of the work demonstrated the necessity of functional testing in validating disease-associated mutations, and added to the catalogue of known BBS disease genes.

Further study into the role of copy-number variations (CNVs) in a cohort of BBS patients showed the significant contribution of CNVs to disease pathology. Using high-density array comparative genomic hybridization (aCGH) we were able to identify pathogenic CNVs as small as several hundred bp. Dissection of constituent gene and in vivo experiments investigating epistatic interactions between affected genes allowed for an appreciation of several paradigms by which CNVs can contribute to disease. This study revealed that the contribution of CNVs to disease in BBS patients is much higher than previously expected, and demonstrated the necessity of consideration of CNV contribution in future (and retrospective) investigations of human genetic disease.

Finally, we used a combination of comparative genomics and in vivo complementation assays to identify second-site compensatory modification of pathogenic alleles. These pathogenic alleles, which are found compensated in other species (termed compensated pathogenic deviations [CPDs]), represent a significant fraction (from 3 – 10%) of human disease-associated alleles. In silico pathogenicity prediction algorithms, a valuable method of allele prioritization, often misrepresent these alleles as benign, leading to omission of possibly informative variants in studies of human genetic disease. We created a mathematical model that was able to predict CPDs and putative compensatory sites, and functionally showed in vivo that second-site mutation can mitigate the pathogenicity of disease alleles. Additionally, we made publically available an in silico module for the prediction of CPDs and modifier sites.

These studies have advanced the ability to interpret the pathogenicity of multiple types of human variation, as well as made available tools for others to do so as well.

The Influence of Geological Process on Interpreting Ediacaran Fossils in the Catalina Formation, Bonavista Peninsula, Newfoundland

Understanding the nature of the earliest complex fossils has presented many challenges over the past century since Billings first described Ediacaran fossils from Newfoundland in 1872. Previous studies have documented abundant Ediacaran fossils in the Bonavista Peninsula of Newfoundland. This thesis focuses on the H14 surface north of Catalina, which contains a nearly monospecific assemblage that includes hundreds of specimens of the rangeomorph, Fractofusus andersoni. Three factors need to be considered when trying to interpret these organisms. The first of these three factors is structural deformation. The area has undergone deformation during the formation of the Appalachian orogenic belt. This has distorted both fossil shape and orientation, requiring retrodeformation to restore the shapes and relationships of fossils to their original form. Two additional taphonomic factors influencing fossil visibility are: partly or completely ash covered fossils and the removal of fossil impressions from the bedding plane by modern weathering. These processes hinder acceptance of some previously published interpretations.

Organizing and Interpreting Unstructured Qualitative Data

In the last several years there has been an increase in the amount of qualitative research using in-depth interviews and comprehensive content analyses in sport psychology. However, no explicit method has been provided to deal with the large amount of unstructured data. This article provides common guidelines for organizing and interpreting unstructured data. Two main operations are suggested and discussed: first, coding meaningful text segments, or creating tags, and second, regrouping similar text segments,or creating categories. Furthermore, software programs for the microcomputer are presented as away to facilitate the organization and interpretation of qualitative data

Cracking the USA? Interpreting UK-to-US TV Drama Translations

For well over half a century, British TV drama production has both inherited from and aimed to appeal to nations and cultures beyond the UK, particularly the lucrative (yet notoriously tough) US TV market. However, in the context of mainstream American broadcasting, British-produced imports have never been anything more than a peripheral presence on US small screens. A currently prominent production strategy aiming to counter the mainstream US TV market's aversion to foreign-sourced drama, in an attempt to access prime-time broadcasting positions, is a process which can be labelled as UK-to-US TV drama ‘translation’: the ‘recreation’ of British-based dramas within an American cultural framework. Whilst the cultural reconfiguration of game show and reality/lifestyle TV formats has received heightened critical attention in recent years, investigation into the international translation of TV drama remains less developed. This paper investigates both the internal textual operations and the external production dynamics involved in the process of UK-to-US TV drama translation, drawing on direct interview material from industry professionals. The UK and US versions of the crime drama Cracker constitute the core translation case study, utilising the close analysis of text and production context as a lens through which to examine the mechanics of UK-to-US TV drama translation.

Some Remarks on Quality in Interpreting, Interpreting Modes and the Interpreter’s Role

Quality in interpreting is a hotly debated issue whose complexity is determined by a mix of factors. In this article I analyze it in the light of the role played by interpreters, stressing how the constraints imposed by the different interpreting modes, the different roles actually played by professionals (who become more or less visible, even within the same assignment) and the expectations they generate require the adoption of a flexible perspective when it comes to identifying and assessing quality criteria and drafting professional codes that are open enough to adjust to diverse communicative settings and to the dynamic character of quality.

Interpreting innovation – in another way

Innovation helps to uncover the future social and economic possibilities. Subsequently familiarising with innovation processes, mapping those involved in innovation and researching the relations and influencing factors is becoming more and more valuable. The authors carried out innovation research in three middle-sized and small towns in Hungary on the basis of a request by a municipality among enterprises involved in the intelligent specialisation strategic program. In the course of the research the role of regional universities, the relationship between organisations involved in social innovation and the researched enterprises, as well as traditional innovation areas were dealt with. The innovation performance of enterprises in all three regions are – despite smaller differences – around the Hungarian average. The presence of a university in the region can be felt, however, it does not remarkably influence the innovation potential of enterprises. It seemed that outside the traditional links to chambers of commerce and industry there were no other civic protagonists in the processes of creating knowledge, and even the relations are rather loose, or mediocre. In the wake of these results, the authors formulated specific suggestions for improving the economic and social possibilities of the involved regions by establishing innovative environments.

A Study of Some Centrality Measures in Graphs

Centrality is in fact one of the fundamental notions in graph theory which has established its close connection with various other areas like Social networks, Flow networks, Facility location problems etc. Even though a plethora of centrality measures have been introduced from time to time, according to the changing demands, the term is not well defined and we can only give some common qualities that a centrality measure is expected to have. Nodes with high centrality scores are often more likely to be very powerful, indispensable, influential, easy propagators of information, significant in maintaining the cohesion of the group and are easily susceptible to anything that disseminate in the network.

An investigation of Hebbian phase sequences as assembly graphs

Hebb proposed that synapses between neurons that fire synchronously are strengthened, forming cell assemblies and phase sequences. The former, on a shorter scale, are ensembles of synchronized cells that function transiently as a closed processing system; the latter, on a larger scale, correspond to the sequential activation of cell assemblies able to represent percepts and behaviors. Nowadays, the recording of large neuronal populations allows for the detection of multiple cell assemblies. Within Hebb's theory, the next logical step is the analysis of phase sequences. Here we detected phase sequences as consecutive assembly activation patterns, and then analyzed their graph attributes in relation to behavior. We investigated action potentials recorded from the adult rat hippocampus and neocortex before, during and after novel object exploration (experimental periods). Within assembly graphs, each assembly corresponded to a node, and each edge corresponded to the temporal sequence of consecutive node activations. The sum of all assembly activations was proportional to firing rates, but the activity of individual assemblies was not. Assembly repertoire was stable across experimental periods, suggesting that novel experience does not create new assemblies in the adult rat. Assembly graph attributes, on the other hand, varied significantly across behavioral states and experimental periods, and were separable enough to correctly classify experimental periods (Naïve Bayes classifier; maximum AUROCs ranging from 0.55 to 0.99) and behavioral states (waking, slow wave sleep, and rapid eye movement sleep; maximum AUROCs ranging from 0.64 to 0.98). Our findings agree with Hebb's view that assemblies correspond to primitive building blocks of representation, nearly unchanged in the adult, while phase sequences are labile across behavioral states and change after novel experience. The results are compatible with a role for phase sequences in behavior and cognition.

Flexible modeling and estimation for high-dimensional graphs

Thesis (Ph.D.)--University of Washington, 2016-08

Unlinked Embedded Graphs

This paper is a self-contained development of an invariant of graphs embedded in three-dimensional Euclidean space using the Jones polynomial and skein theory. Some examples of the invariant are computed. An unlinked embedded graph is one that contains only trivial knots or links. Examples show that the invariant is sufficiently powerful to distinguish some different unlinked embeddings of the same graph.

Real-time analytics on large dynamic graphs

In today's fast-paced and interconnected digital world, the data generated by an increasing number of applications is being modeled as dynamic graphs. The graph structure encodes relationships among data items, while the structural changes to the graphs as well as the continuous stream of information produced by the entities in these graphs make them dynamic in nature. Examples include social networks where users post status updates, images, videos, etc.; phone call networks where nodes may send text messages or place phone calls; road traffic networks where the traffic behavior of the road segments changes constantly, and so on. There is a tremendous value in storing, managing, and analyzing such dynamic graphs and deriving meaningful insights in real-time. However, a majority of the work in graph analytics assumes a static setting, and there is a lack of systematic study of the various dynamic scenarios, the complexity they impose on the analysis tasks, and the challenges in building efficient systems that can support such tasks at a large scale. In this dissertation, I design a unified streaming graph data management framework, and develop prototype systems to support increasingly complex tasks on dynamic graphs. In the first part, I focus on the management and querying of distributed graph data. I develop a hybrid replication policy that monitors the read-write frequencies of the nodes to decide dynamically what data to replicate, and whether to do eager or lazy replication in order to minimize network communication and support low-latency querying. In the second part, I study parallel execution of continuous neighborhood-driven aggregates, where each node aggregates the information generated in its neighborhoods. I build my system around the notion of an aggregation overlay graph, a pre-compiled data structure that enables sharing of partial aggregates across different queries, and also allows partial pre-computation of the aggregates to minimize the query latencies and increase throughput. Finally, I extend the framework to support continuous detection and analysis of activity-based subgraphs, where subgraphs could be specified using both graph structure as well as activity conditions on the nodes. The query specification tasks in my system are expressed using a set of active structural primitives, which allows the query evaluator to use a set of novel optimization techniques, thereby achieving high throughput. Overall, in this dissertation, I define and investigate a set of novel tasks on dynamic graphs, design scalable optimization techniques, build prototype systems, and show the effectiveness of the proposed techniques through extensive evaluation using large-scale real and synthetic datasets.

OVERCOMING INTERCULTURAL CHALLENGES IN INTERPRETING: A CASE STUDY ON CHINESE-ENGLISH CONFERENCE INTERPRETING

This exploratory case study examines the role of culture in Chinese-English conference interpreting. Given that there has been a lack of empirical research in understanding the role of culture in conference interpreting through the lens of intercultural communication frameworks, we know relatively little about conference interpreters’ experiences with intercultural communication challenges. This project helps address this research gap by investigating the types of intercultural communication challenges that Chinese-English conference interpreters experience and their strategies in managing those challenges. This study hears the voices of both professionals and postgraduate interpreting students. A total number of 27 participants were recruited for this research. Twenty professional conference interpreter were interviewed and seven interpreting students were organized for a focus group discussion. Grounded theory was used to analyze the participants’ observations and strategies in managing intercultural communication challenges when doing Chinese-English conference interpreting. The data analysis process led to the emergence of two procedural guidelines and one process – Interpreters’ Intercultural Mediation Process. The two procedural guidelines offer guidance for the interpreters to provide the most appropriate and effective service: meet with the clients beforehand and be prepared to offer intercultural insights when consulted. Interpreters are found to follow the Interpreters’ Intercultural Mediation Process to decide when and how to mediate intercultural communication challenges at work. This Process includes four criteria, seven intercultural challenges, and seven coping strategies. This study offers theoretical and applied contributions to our understanding of the role of culture in interpreting. By jointly applying frameworks from intercultural communication and interpreting studies to examine the conference interpreting process, this case study makes great efforts to connect the field of intercultural communication with the field of interpreting studies. This study identifies the types of intercultural differences that would lead to challenges in Chinese-English conference interpreting. It also contributes to the call for a cultural turn in interpreting studies. By learning the two procedural guidelines, conference interpreters can be better prepared for their work. By following the Interpreters’ Intercultural Mediation Process, conference interpreters can better anticipate and manage the intercultural challenges at work. This study also offers guidance on tailoring intercultural communication courses for postgraduate interpreting training programs.

Expedition in Data and Harmonic Analysis on Graphs

The graph Laplacian operator is widely studied in spectral graph theory largely due to its importance in modern data analysis. Recently, the Fourier transform and other time-frequency operators have been defined on graphs using Laplacian eigenvalues and eigenvectors. We extend these results and prove that the translation operator to the i’th node is invertible if and only if all eigenvectors are nonzero on the i’th node. Because of this dependency on the support of eigenvectors we study the characteristic set of Laplacian eigenvectors. We prove that the Fiedler vector of a planar graph cannot vanish on large neighborhoods and then explicitly construct a family of non-planar graphs that do exhibit this property. We then prove original results in modern analysis on graphs. We extend results on spectral graph wavelets to create vertex-dyanamic spectral graph wavelets whose support depends on both scale and translation parameters. We prove that Spielman’s Twice-Ramanujan graph sparsifying algorithm cannot outperform his conjectured optimal sparsification constant. Finally, we present numerical results on graph conditioning, in which edges of a graph are rescaled to best approximate the complete graph and reduce average commute time.