Globalisation and the quest for competitiveness in a global market represents a new era of connectedness within public-private networks of experts in an effort to pursue research objectives in advanced technology industries. Balancing the competing interests of public good and private gain, reducing the barriers in terms of access to knowledge and intellectual property and ensuring that efforts result in socially valuable outcomes in the form of new innovations can be difficult, to say the least. <p>Although widely advocated and implemented, collaborations have not, as yet, been fully examined nor have appropriate performance evaluation models been developed to evaluate them. This dissertation hypothesizes that a history of social relationships or collaborative activity amongst network actors is positively correlated with high performance in networks. Incorporating descriptive statistics with the social network analysis tool, this dissertation proposes and tests a novel framework and compares two distinct Genome Canada funded research networks. Other factors explored are the roles of proximity, institution and research focus in characterizing network structure and in affecting performance.

Bloom syndrome is a rare autosomal recessive disorder that is caused by mutations in the BLM gene. BLM associates with TopoIIIα and RMI1 to form a complex that is essential to maintain genome integrity. This complex catalyzes a dissolution reaction that resolves recombination intermediates containing two Holliday junctions without crossing over of genetic material. Dissolution activity is remarkable because it accounts for the in vivo role of BLM-TopoIIIα-RMI1 in suppressing sister chromatid exchanges. To further understand the biochemical roles that each member of the BLM complex plays in dissolution, I generated single-stranded catenanes that resemble the proposed intermediates at the latest steps of dissolution. Using this substrate, I demonstrated that TopoIIIα is a single-stranded DNA decatenase that is specifically stimulated by BLM and RMI1. Interaction between TopoIIIα and RMI1 is essential for the optimal decatenase activity. Furthermore, binding of RPA to single-stranded DNA substrate inhibits TopoIIIα decatenase activity. However, complex formation between BLM, TopoIIIα and RMI enables TopoIIIα to displace RPA and catalyze decatenation. Since the decatenase activity is presumed to be involved in many aspects of DNA metabolism, I investigated the roles of RMI1 and TopoIIIα in DNA replication in vivo. Using the molecular combing technique, I showed that RMI1 functions downstream of BLM to promote normal replication fork progression. In addition, BLM, TopoIIIα and RMI1 colocalize with one another in response to replication stress. Finally, interaction between TopoIIIα and RMI1 is essential for nuclear localization of the complex and for the complex to promote recovery from replication stress. This work defines molecular functions for RMI1 and TopoIIIα in DNA replication and repair, providing insight into their roles as suppressors of genome instability.

Clostridium scatologenes is an anaerobic bacterium that demonstrates some unusual metabolic traits such as the production of 3-methyl indole. The availability of genome level sequencing has lent itself to the exploration and elucidation of unique metabolic pathways in other organisms such as Clostridium botulinum. The Clostridium scatologenes genome, with an estimated length 4.2 million bp, was sequenced by the Applied Biosystems Solid method and the Roche 454 pyrosequencing method. The resulting DNA sequences were combined and assembled into 8267 contigs with an average length of 1250 bp with the Newbler Assembler program. Comparision of published subunits of csd gene and assembled contigs identified that one contig contained all three subunits. In addition a gene with similarity to clostridium carboxidivorans butyrate kinase was found lined next to csd gene. An alignment of the contig and csdgene sequences identified three deletions in the contig within the 4066 bases of the alignment. This implies that there is about 0.07% error rate in the sequencing itself requiring more finishing. Even without finishing the genome assembly into single contig, contigs were annotated in RAST pipeline predicting 2521 protein encoding genes (PEGs). The PEGs were classified by their metabolic function and compared to classified PEGs found in the closely related clostridium species, Clostridium carboxidivorans and Clostridium. ljungdahlii, which have similarly sized genomes. According to the RAST analysis, Clostridium scatologenes had 35% subsystem coverage of all known metabolic processes with its 2521 PEGs. This compares to 41% for Clostridium carboxidivorans with 4174 PEGs (29) and 42% for Clostridium ljungdahlii with 4184 PEGs (30), indicating that Clostridium scatologenesmay still have more genes to be identified. Comparison of the percent genes found in the metabolic subsystems was similar except in motility and chemotaxis. The contigs, on which the csd gene and tryptophan metabolizing genes lay, were examined to see if additional genes might support these metabolic pathways. Butyrate kinase was associated with the csd genes but no other associations were found for the two tryptophan metabolizing genes. The tryptophan biosynthesis operon genes were all found on one contig (contig 6771) and were syntenic with other bacterial species.

The genomic diversity of viral quasispecies is a subject of great interest, especially for chronic infections. Characterization of viral diversity can be addressed by high-throughput sequencing technology (454 Life Sciences, Illumina, SOLiD, Ion Torrent, etc.). Standard assembly software was originally designed for single genome assembly and cannot be used to assemble and estimate the frequency of closely related quasispecies sequences. This work focuses on parsimonious and maximum likelihood models for assembling viral quasispecies and estimating their frequencies from 454 sequencing data. Our methods have been applied to several RNA viruses (HCV, IBV) as well as DNA viruses (HBV), genotyped using 454 Life Sciences amplicon and shotgun methods.

The genomic diversity of viral quasispecies is a subject of great interest, especially for chronic infections. Characterization of viral diversity can be addressed by high-throughput sequencing technology (454 Life Sciences, Illumina, SOLiD, Ion Torrent, etc.). Standard assembly software was originally designed for single genome assembly and cannot be used to assemble and estimate the frequency of closely related quasispecies sequences. This work focuses on parsimonious and maximum likelihood models for assembling viral quasispecies and estimating their frequencies from 454 sequencing data. Our methods have been applied to several RNA viruses (HCV, IBV) as well as DNA viruses (HBV), genotyped using 454 Life Sciences amplicon and shotgun methods.

Globalisation and the quest for competitiveness in a global market represents a new era of connectedness within public-private networks of experts in an effort to pursue research objectives in advanced technology industries. Balancing the competing interests of public good and private gain, reducing the barriers in terms of access to knowledge and intellectual property and ensuring that efforts result in socially valuable outcomes in the form of new innovations can be difficult, to say the least. <p>Although widely advocated and implemented, collaborations have not, as yet, been fully examined nor have appropriate performance evaluation models been developed to evaluate them. This dissertation hypothesizes that a history of social relationships or collaborative activity amongst network actors is positively correlated with high performance in networks. Incorporating descriptive statistics with the social network analysis tool, this dissertation proposes and tests a novel framework and compares two distinct Genome Canada funded research networks. Other factors explored are the roles of proximity, institution and research focus in characterizing network structure and in affecting performance.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 150-166). Also available in print.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Vita. Includes bibliographical references. Available also from UMI Company.

This dissertation presents the result of two separate research programs. The first elucidates the phylogeny, biogeography and systematics of the genus Menodora in the olive family. A phylogeny based on the internal transcribed spacer (ITS) of nuclear ribosomal DNA and the chloroplast rps16 and trnL introns and trnL-F intergenic spacer demonstrates that the genus is monophyletic. Within the genus, M. robusta of Patagonia is the first taxon to branch, followed by a monophyletic African clade and M. spinescens of California, though the placement of the latter does not have strong support. Most North American species are nested within the derived South Americans. A South American origin is hypothesized, with two independent dispersals to North America, and a single dispersal to Africa. The phylogeny provided new insights for the systematic treatment, where 24 species, one subspecies and six varieties are recognized, with major realignments of the intregrifolia and scabra species complexes, and a single new species described. In the second area of research, the chloroplast genome of Pelargonium × hortorum has been completely sequenced. At 217,942 base pairs (bp), it is both the largest and most rearranged land plant chloroplast genome yet sequenced. It features two copies of a greatly expanded inverted repeat (IR) of 75,741 bp each, and diminished single copy regions of 59,710 bp and 6,750 bp. Gene content is similar to other angiosperms, with the exceptions of a large number of pseudogenes, two open reading frames (ORF56 and ORF42), and the losses of accD, trnT-ggu, and possibly rpoA. The latter may be represented, however, by highly divergent set of rpoA-like ORFs. The IR expansion accounts for most of the size increase of the genome, but an additional 10% is related to the large number of repeats found. Most of these occur near rearrangement hotspots, and two different repeat associations (characterized by full or partial duplications of several genes) are localized in these regions. We propose simple models that account for the major rearrangements with a minimum of eight IR boundary changes and 12 inversions in addition to several sequence duplications. / text

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