The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data

The relationship between major depressive disorder (MDD) and bipolar disorder (BD) remains controversial. Previous research has reported differences and similarities in risk factors for MDD and BD, such as predisposing personality traits. For example, high neuroticism is related to both disorders, whereas openness to experience is specific for BD. This study examined the genetic association between personality and MDD and BD by applying polygenic scores for neuroticism, extraversion, openness to experience, agreeableness and conscientiousness to both disorders. Polygenic scores reflect the weighted sum of multiple single-nucleotide polymorphism alleles associated with the trait for an individual and were based on a meta-analysis of genome-wide association studies for personality traits including 13,835 subjects. Polygenic scores were tested for MDD in the combined Genetic Association Information Network (GAIN-MDD) and MDD2000+ samples (N=8921) and for BD in the combined Systematic Treatment Enhancement Program for Bipolar Disorder and Wellcome Trust Case-Control Consortium samples (N=6329) using logistic regression analyses. At the phenotypic level, personality dimensions were associated with MDD and BD. Polygenic neuroticism scores were significantly positively associated with MDD, whereas polygenic extraversion scores were significantly positively associated with BD. The explained variance of MDD and BD, approximately 0.1%, was highly comparable to the variance explained by the polygenic personality scores in the corresponding personality traits themselves (between 0.1 and 0.4%). This indicates that the proportions of variance explained in mood disorders are at the upper limit of what could have been expected. This study suggests shared genetic risk factors for neuroticism and MDD on the one hand and for extraversion and BD on the other.

Controlling transduction and replication of oncolytic adenoviruses

Despite progress in conventional cancer treatment regimes, metastatic disease essentially remains incurable and new treatment alternatives are needed. Virotherapy is a relatively novel approach in cancer treatment. It harnesses the natural ability of oncolytic viruses to kill the cells they proliferate in and to spread to neighboring cells, thereby amplifying the therapeutic effect of the initial input dose. The use of replicating, oncolytic viruses for cancer treatment necessitates introduction of various genetic modifications to the viral genome, thereby restraining replication exclusively to tumor cells and eventually obtaining selective eradication of the tumor without side effects to healthy tissue. Furthermore, various modifications can be applied to the viral capsid in hope of gaining effective transduction of target tissue. In other words, the entry of viruses into tumor tissue can be augmented by allowing the virus to utilize non-native receptors for entry. Genetic capsid modifications may also help to avoid some major hurdles in systemic delivery that ultimately lead to the rapid clearance of the virus from the blood and virus induced toxicity. In addition to genetic modifications that alter the phenotype of the virus, some pharmacologic agents may be utilized to enhance the virus entry to target site. Liver kupffer cells (KC) are responsible for the majority of viral clearance after systemic viral delivery and they play a major role in adenovirus induced acute toxicity. The therapeutic window could possibly be widened by transiently depleting KCs, allowing smaller viral input doses and diminishing KC related toxicity. The transductional efficacy of various capsid modified viruses was analyzed in vitro and in vivo in murine orthotopic breast cancer model. The effect of capsid modifications on the oncolytic efficacy, i.e. the ability of the viruses to kill cancer cells, was evaluated in vitro and in vivo in murine cancer models. We concluded that capsid modifications result in transductional enhancement, and that enhanced transduction translates into more potent oncolysis in vitro and in vivo. When KC depleting agents were used in vivo prior to viral injections, enhanced tumor transduction was seen, but this effect was not translated into enhanced antitumor activity. Transcriptional regulation of replicative oncolytic viruses is a prerequisite for virotherapy. Tumor or tissue specific promoters can be used to control the transcription of adenoviral early genes to gain cancer specific viral replication. Specific deletions in viral regions essential for virus replication in normal cells can further increase the safety by allowing viral genome replication in cancer cells featuring specific mutations. Genetically modified viruses were shown to be able to kill putative cancer stem cells that are thought to be responsible for post treatment relapses and metastasis. Further, pharmacologic intervention reduced viral replication and thereby might offer an additional safety switch in case viral replication related side effects are encountered.

Selection of Corymbia citriodora for pulp productivity

Evaluation of a series of spotted gum (Corymbia citirodora) progeny trials, established in the subtropical region of Queensland, Australia, was undertaken to provide information for the development of advanced-generation breeding populations suitable for pulp production. Measurements of growth at two ages were combined with assessments of wood density and pulp yield from a selected sample of provenances to provide comparisons between provenances, to generate genetic parameter estimates and to predict genetic gain potential. Although growth at this age was moderate relative to other eucalypts, the near-infrared predictions of average wood density of 756 kg m(-3) and pulp yield of 55% indicate the species has considerable potential as a pulpwood crop. A pulp productivity breeding objective was used to identify production populations using a range of selection trait weightings to determine potential genetic gain for pulp productivity. Genetic parameters indicated (1) levels of genetic control were moderate for all traits and higher for wood property traits, (2) genetic improvements could be achieved by selection among and within provenances with greater levels of improvement available from selection within populations, (3) genotype by environment interactions were negligible, (4) genetic correlations between traits were favourable, and (5) selection of volume production alone would maximise improvements in pulp productivity.

Species-based and community-level approaches to conservation prioritization

One major reason for the global decline of biodiversity is habitat loss and fragmentation. Conservation areas can be designed to reduce biodiversity loss, but as resources are limited, conservation efforts need to be prioritized in order to achieve best possible outcomes. The field of systematic conservation planning developed as a response to opportunistic approaches to conservation that often resulted in biased representation of biological diversity. The last two decades have seen the development of increasingly sophisticated methods that account for information about biodiversity conservation goals (benefits), economical considerations (costs) and socio-political constraints. In this thesis I focus on two general topics related to systematic conservation planning. First, I address two aspects of the question about how biodiversity features should be valued. (i) I investigate the extremely important but often neglected issue of differential prioritization of species for conservation. Species prioritization can be based on various criteria, and is always goal-dependent, but can also be implemented in a scientifically more rigorous way than what is the usual practice. (ii) I introduce a novel framework for conservation prioritization, which is based on continuous benefit functions that convert increasing levels of biodiversity feature representation to increasing conservation value using the principle that more is better. Traditional target-based systematic conservation planning is a special case of this approach, in which a step function is used for the benefit function. We have further expanded the benefit function framework for area prioritization to address issues such as protected area size and habitat vulnerability. In the second part of the thesis I address the application of community level modelling strategies to conservation prioritization. One of the most serious issues in systematic conservation planning currently is not the deficiency of methodology for selection and design, but simply the lack of data. Community level modelling offers a surrogate strategy that makes conservation planning more feasible in data poor regions. We have reviewed the available community-level approaches to conservation planning. These range from simplistic classification techniques to sophisticated modelling and selection strategies. We have also developed a general and novel community level approach to conservation prioritization that significantly improves on methods that were available before. This thesis introduces further degrees of realism into conservation planning methodology. The benefit function -based conservation prioritization framework largely circumvents the problematic phase of target setting, and allowing for trade-offs between species representation provides a more flexible and hopefully more attractive approach to conservation practitioners. The community-level approach seems highly promising and should prove valuable for conservation planning especially in data poor regions. Future work should focus on integrating prioritization methods to deal with multiple aspects in combination influencing the prioritization process, and further testing and refining the community level strategies using real, large datasets.

A promoter-level mammalian expression atlas

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

Allosteric Communication in Cysteinyl tRNA Synthetase A NETWORK OF DIRECT AND INDIRECT READOUT

Protein structure networks are constructed for the identification of long-range signaling pathways in cysteinyl tRNA synthetase (CysRS). Molecular dynamics simulation trajectory of CysRS-ligand complexes were used to determine conformational ensembles in order to gain insight into the allosteric signaling paths. Communication paths between the anticodon binding region and the aminoacylation region have been identified. Extensive interaction between the helix bundle domain and the anticodon binding domain, resulting in structural rigidity in the presence of tRNA, has been detected. Based on the predicted model, six residues along the communication paths have been examined by mutations (single and double) and shown to mediate a coordinated coupling between anticodon recognition and activation of amino acid at the active site. This study on CysRS clearly shows that specific key residues, which are involved in communication between distal sites in allosteric proteins but may be elusive in direct structure analysis, can be identified from dynamics of protein structure networks.

Polimorfismos do gene da tiopurina metiltransferase (TPMT) em pacientes com doenças inflamatórias intestinais: avaliação da prevalência e correlação com efeitos colaterais

A azatioprina e a 6 mercaptopurina (6-MCP) são drogas muito utilizada no tratamento das doenças inflamatórias intestinais (DII), porém estão associadas a vários efeitos colaterais. A determinação prévia do genótipo da tiopurina metiltransferase (TPMT) pode identificar pacientes de maior risco de toxicidade a droga. Os objetivos deste estudo foram avaliar a prevalência dos polimorfismos do gene da TPMT em pacientes com DII acompanhados no Hospital Universitário Pedro Ernesto (HUPE) da UERJ, comparando com a prevalência em outras populações e correlacionar a presença desses polimorfismos com a toxicidade às drogas. Foram avaliados 146 pacientes com doença de Crohn (DC) e 73 com retocolite ulcerativa idiopática (RCUI). A pesquisa dos principais genótipos da TPMT (*2, *3, *3C) foi realizada por técnicas de PCR (alelo específico e RFLP). Os achados clínicos foram correlacionados com a genotipagem e avaliados por análises multivariadas. Dentre os pacientes que estavam em uso de azatioprina, 14 apresentaram pancreatite ou elevação de enzimas pancreáticas, 6 apresentaram hepatoxicidade e 2 evoluíram com neutropenia. Os polimorfismos do gene da TPMT foram observados em 37 dos 219 pacientes (8 foram heterozigotos para o genótipo *2, 11 heterozigotos para *3A e 18 foram heterozigotos para o polimorfismo *3C). Não foi observado nenhum homozigoto polimórfico. Uma correlação positiva foi observada entre a elevação de enzimas pancreáticas e os genótipos *2 e *3C. A prevalência dos polimorfismos neste estudo (16,89%) foi maior que a descrita para população caucasiana e em outros estudos brasileiros. Apesar do predomínio do genótipo *3C, não houve ocorrência exclusiva de um polimorfismo, conforme observado em outras populações. A população brasileira devido à sua miscigenação têm características genotípicas próprias diferentes do outros países do mundo. Dois polimorfismos da TPMT (*2 e *3C) estiveram associados à toxicidade ao uso da azatioprina em pacientes com DII no sudeste do Brasil. O teste genético pode auxiliar na escolha da melhor droga e na dose ideal para os pacientes portadores de DII antes do início do tratamento.

Pacific Salmon, Oncorhynchus spp., and the Definition of "Species" Under the Endangered Species Act

For purposes ofthe Endangered Species Act (ESA), a "species" is defined to include "any distinct population segment of any species of vertebrate fish or wildlife which interbreeds when mature. "Federal agencies charged with carrying out the provisions of the ESA have struggled for over a decade to develop a consistent approach for interpreting the term "distinct population segment." This paper outlines such an approach and explains in some detail how it can be applied to ESA evaluations of anadromous Pacific salmonids. The following definition is proposed: A population (or group of populations) will be considered "distinct" (and hence a "species ")for purposes of the ESA if it represents an evolutionarily significant unit (ESU) of the biological species. A population must satisfy two criteria to be considered an ESU: 1) It must be substantially reproductively isolated from other conspecific population units, and 2) It must represent an important component in the evolutionary legacy of the species. Isolation does not have to be absolute, but it must be strong enough to permit evolutionarily important differences to accrue in different population units. The second criterion would be met if the population contributes substantially to the ecological/genetic diversity of the species as a whole. Insights into the extent of reproductive isolation can be provided by movements of tagged fish, natural recolonization rates observed in other populations, measurements of genetic differences between populations, and evaluations of the efficacy of natural barriers. Each of these methods has its limitations. Identification of physical barriers to genetic exchange can help define the geographic extent of distinct populations, but reliance on physical features alone can be misleading in the absence of supporting biological information. Physical tags provide information about the movements of individual fish but not the genetic consequences of migration. Furthermore, measurements ofc urrent straying or recolonization rates provide no direct information about the magnitude or consistency of such rates in the past. In this respect, data from protein electrophoresis or DNA analyses can be very useful because they reflect levels of gene flow that have occurred over evolutionary time scales. The best strategy is to use all available lines of evidence for or against reproductive isolation, recognizing the limitations of each and taking advantage of the often complementary nature of the different types of information. If available evidence indicates significant reproductive isolation, the next step is to determine whether the population in question is of substantial ecological/genetic importance to the species as a whole. In other words, if the population became extinct, would this event represent a significant loss to the ecological/genetic diversity of thes pecies? In making this determination, the following questions are relevant: 1) Is the population genetically distinct from other conspecific populations? 2) Does the population occupy unusual or distinctive habitat? 3) Does the population show evidence of unusual or distinctive adaptation to its environment? Several types of information are useful in addressing these questions. Again, the strengths and limitations of each should be kept in mind in making the evaluation. Phenotypic/life-history traits such as size, fecundity, and age and time of spawning may reflect local adaptations of evolutionary importance, but interpretation of these traits is complicated by their sensitivity to environmental conditions. Data from protein electrophoresis or DNA analyses provide valuable insight into theprocessofgenetic differentiation among populations but little direct information regarding the extent of adaptive genetic differences. Habitat differences suggest the possibility for local adaptations but do not prove that such adaptations exist. The framework suggested here provides a focal point for accomplishing the majorgoal of the Act-to conserve the genetic diversity of species and the ecosystems they inhabit. At the same time, it allows discretion in the listing of populations by requiring that they represent units of real evolutionary significance to the species. Further, this framework provides a means of addressing several issues of particular concern for Pacific salmon, including anadromous/nonanadromous population segments, differences in run-timing, groups of populations, introduced populations, and the role of hatchery fish.