京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18803号 / 理博第4061号 / 新制||理||1584(附属図書館) / 31754 / 京都大学大学院理学研究科地球惑星科学専攻 / (主査)教授 平田 岳史, 教授 田上 高広, 教授 土`山 明 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

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This dissertation is a primarily theoretical study of self-organization, through which a constellation of organizations can control the process of strategic adaptation in the paradigm shift. Curiously, existing theories about the control mechanism seem to be insufficient to address the problems of control seriously in the pre-paradigmatic state. The dissertation includes three main chapters of literature review, theoretical analysis, and case study. The extensive literature review provides a fertile foundation to support this study. The chapter of theoretical analysis aims to theorize about self-organization as a new control mechanism. The case study chapter seeks to address the new conceptual model and its application to the phenomenon. Consequently, the dissertation not only presents a detailed comparison of existing theories but also elaborates the new model of control mechanism. This study considers the phenomenon of manufacturing without a factory as the evidence of the controlled system without governance structure in the paradigm shift. Through the content analysis method, the case study analyzes how differently IBM and Apple, Inc. have controlled manufacturing processes entirely outsourced to external partners and why IBM failed the challenges while Apple could succeed. The theoretical analysis addresses why firms must manage external adjustment processes and be agile with the high capacity of information processing as a constellation of organizations grows. This study will shed lights on uncovering the management of postmodern organizations in the twenty-first century. / Business Administration/Strategic Management

The mechanism through which the Appalachian Mountains have maintained moderate relief some ~300 Myr after the cessation of mountain building has long puzzled geomorphologists. As recent studies have shown that Appalachian exhumation has occurred at slow rates consistent with isostatic rebound of thickened crust, the driving forces behind localized episodes of accelerated incision and the associated rugged topography have been difficult to explain given the absence of tectonic uplift. This study uses previously undocumented relict fluvial gravels and knickpoint location to confirm the role of drainage rearrangement in producing local base level drop and subsequent basin-scale transient incision in the southern Appalachians. This process is fundamentally driven by the high potential energy of streams flowing across the elevated, slowly eroding Blue Ridge Plateau relative to the present Atlantic and landward interior base levels. Gravel deposits confirm that repeated capture of landward-draining Plateau streams by Atlantic basin streams, whose immediate base level is 250-300 m lower, forces episodic rapid incision and overall erosional retreat of the Blue Ridge Escarpment along the Plateau margin. The distribution of knickpoints, bedrock gorges, and relict surfaces in the interior of the Plateau indicate that the New River, which drains to the continental interior, is actively incising the low-relief Plateau surface due to episodic drops in landward base level. The origin of landward base level perturbation is unclear, but it may be the result of glacially-driven shortening and steepening of the lower New River during the Pleistocene. Collectively, these data indicate that rapid base level drop through drainage reorganization can energize streams in otherwise stable landscapes and accelerate fluvial incision and relief production without uplift of the land surface. This process is likely quite significant in post-orogenic settings, where inherited drainage patterns may not reflect the most direct, and thus energetically appropriate, path to present base level. Passive margins may therefore never achieve a topographic steady-state, despite uniformly slow and constant uplift due to isostatic rebound. / Ph. D.

The data from genome-wide association studies (GWAS) in humans are still predominantly analyzed using single marker association methods. As an alternative to Single Marker Analysis (SMA), all or subsets of markers can be tested simultaneously. This approach requires a form of Penalized Regression (PR) as the number of SNPs is much larger than the sample size. Here we review PR methods in the context of GWAS, extend them to perform penalty parameter and SNP selection by False Discovery Rate (FDR) control, and assess their performance (including penalties incorporating linkage disequilibrium) in comparison with SMA. PR methods were compared with SMA on realistically simulated GWAS data consisting of genotype data from single and multiple chromosomes and a continuous phenotype and on real data. Based on our comparisons our analytic FDR criterion may currently be the best approach to SNP selection using PR for GWAS. We found that PR with FDR control provides substantially more power than SMA with genome-wide type-I error control but somewhat less power than SMA with Benjamini-Hochberg FDR control. PR controlled the FDR conservatively while SMA-BH may not achieve FDR control in all situations. Differences among PR methods seem quite small when the focus is on variable selection with FDR control. Incorporating LD into PR by adapting penalties developed for covariates measured on graphs can improve power but also generate morel false positives or wider regions for follow-up. We recommend using the Elastic Net with a mixing weight for the Lasso penalty near 0.5 as the best method. / Ph. D.

A associação não aleatória entre alelos de diferentes lócus caracteriza o que é chamado de desequilíbrio de ligação (DL) entre eles. A extensão do DL nas populações humanas pode ser influenciada por muitos fatores, tais como taxa de recombinação, características demográficas (idade, tamanho e taxa de crescimento) e fatores evolutivos (deriva genética, efeito fundador, gargalos populacionais, mutação, seleção e fluxo gênico). Portanto, o conhecimento dos padrões do DL fornecem dados que auxiliam na descrição dos eventos demográficos e evolutivos sofridos pelas populações. O objetivo deste estudo foi descrever os padrões de DL de quatro populações brasileiras e correlacioná-los com suas respectivas histórias demográficas, uma vez que estas populações experimentaram alguns dos eventos evolutivos que geram ou retardam o decréscimo do DL, como fundação por poucos indivíduos, miscigenação no momento da fundação e posterior isolamento. Foram analisadas amostras de três populações remanescentes de quilombos do Estado do Piauí, Gaucinha (GAU, n = 14), Mimbó (MIB, n = 15) e Sítio Velho (STV, n = 15) e da população urbana de Teresina, Piauí (TES, n = 15), além de sete amostras populacionais do projeto HapMap (CEU, CHB, JPT, ASW, LWK, MKK, YRI, todas com n = 15). Foram genotipados mais de 250 mil SNPs (Single Nucleotide Polymorphisms) utilizando-se o GeneChip® Human Mapping 250K Nsp I Array - Affymetrix® nas amostras das quatro populações brasileiras. Os dados brutos das populações do HapMap para este array foram obtidos na página do projeto. Os genótipos para todas as amostras foram determinados pelo algoritmo CRLMM após comparação com o algoritmo BRLMM, e as análises de DL e determinação dos blocos de haplótipos foram realizadas com o uso do programa Haploview. Considerando-se o número de blocos de haplótipos detectados em cada população estudada, padrão semelhante foi observado em todos os autossomos. Em geral, a população europeia (CEU) e as duas populações asiáticas (CHB e JPT) do HapMap apresentaram os maiores números de blocos, enquanto que os menores números foram observados nos quilombos GAU e MIB e na população TES. As populações africanas LWK, MKK e YRI e a população afro-americana ASW apresentaram os valores intermediários e a população afro-brasileira STV, apresentou um número de blocos apenas inferior a CEU, CHB e JPT. A grande contribuição africana nos quilombos GAU e MIB pode explicar o menor DL observado nestas comunidades. Por outro lado, o menor DL em TES se deve, provavelmente, à sua fundação, que envolveu um maior número de indivíduos e foi seguida por um rápido crescimento. A possível explicação para o maior DL observado em STV, em relação aos demais quilombos, consiste em sua peculiar história demográfica: esta comunidade experimentou uma miscigenação no momento de sua fundação, que foi seguida por um crescimento lento e pouca diferenciação. Assim, foi demonstrado como os eventos demográficos de cada população influenciam seus respectivos padrões de DL. / The non-random association between alleles of different loci characterizes what is called linkage disequilibrium (LD) between them. The LD extent in human populations can be influenced by many factors, such as recombination rate, demographic features (age, size and growth rate) and evolutionary events (genetic drift, founder effects, population bottlenecks, mutation, selection and gene flow). Therefore, knowledge of the LD patterns provides data that assists in describing the evolutionary and demographic events experienced by populations. The aim of this study was to describe the LD patterns of four Brazilian populations and correlate these patterns with their respective demographic histories, since these populations have experienced some of the evolutionary events that produce or retard the LD decrease, such as foundation by few individuals, admixture at the founding moment and subsequent isolation. Samples from three quilombo remnants populations of the Piauí State, Gaucinha (GAU, n = 14), Mimbó (MIB, n = 15) and Sítio Velho (STV, n = 15) and the urban population of Teresina, Piauí (TES, n = 15), and seven population samples from the HapMap Project (CEU, CHB, JPT, ASW, LWK, MKK, YRI, all with n = 15) were analyzed. More than 250 thousand SNPs (Single Nucleotide Polymorphisms) were genotyped using the GeneChip ® Human Mapping 250K Nsp Array I - Affymetrix ® in the samples of the four Brazilian populations. Raw data of the HapMap population samples for this array were obtained from the HapMap homepage. Genotypes for all samples were determined by CRLMM algorithm after comparison with the BRLMM algorithm. LD analyzes and determination of haplotype blocks were performed using the Haploview software. Considering the number of haplotype blocks detected in each population, a consistent pattern was observed for all autosomes. The European population (CEU) and the two Asian populations (CHB and JPT) of the HapMap showed the highest numbers of blocks, while the lowest numbers were observed in the GAU and MIB quilombos and in the TES population. The African populations, LWK, MKK and YRI, and the African-American ASW exhibited intermediate values and the African-Brazilian population STV, presented a number of blocks smaller than that observed for CEU, CHB and JPT. The great African contribution in the GAU and MIB quilombos may explain the lower LD observed in these communities. On the other hand, the lower LD in TES is probably due to its foundation that involved a larger number of individuals and was followed by a fast growth. A possible explanation for the higher LD observed in STV, compared to other quilombos, consists in its particular demographic history: this community experienced admixture at the time of its foundation, which was followed by slow growth and low differentiation. Thus, it was shown how the demographic events of each population influence their respective LD patterns.

Submitted by Luciana Ferreira (lucgeral@gmail.com) on 2014-08-06T15:10:39Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Elaine Lima Trigueiro.pdf: 2172405 bytes, checksum: 872d4e471b17e830b4eafc478bfb3cf5 (MD5) / Made available in DSpace on 2014-08-06T15:10:39Z (GMT). No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Elaine Lima Trigueiro.pdf: 2172405 bytes, checksum: 872d4e471b17e830b4eafc478bfb3cf5 (MD5) Previous issue date: 2007 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / Cellulose is one of the most important and the most abundant biopolymer on the planet, playing a key role on the evolutionary history of plants. Important advances have been made in recent years, in particular on the identification of genes and co- expressed genes for the formation of cellulose in the primary and secondary cellular walls of plants. In addition to its biological relevance, cellulose has a great economic importance, not only in Brazil but in the world, especially due to the production of cellulose and paper from Eucalyptus. The high levels of production and competition in the international market are guaranteed by great investments, which are carried through by the forestal sector, in particular by the Genolyptus Project – Brazilian Network for Research on Eucalyptus Genome. This project is the result of a collective effort of companies involved on the production of cellulose and paper and various public research institutions. Their main goal is to identify and characterize genes involved in wood formation with the intent to genetically improve Eucalyptus. Based on this goal, this work was developed with two objectives. The first is doing a preliminary characterization of the cellulose synthase gene in Eucalyptus, which is associated with the synthesis of the secondary cellular wall and is orthologous to the gene EgCeA2, of E. grandis. The second objective is to study the linkage disequilibrium in another gene of cellulose synthase, orthologous to the EgCesA3 gene, sampled from a wild population of E. urophylla. Regarding the CesA2 gene, an exonic region with 427bp was sequenced from DNA samples of 12 individuals from different species and geographic regions. The next step was to proceed with an analysis to detect polymorphism which gave an estimate of three SNPs synonymous along the contig, with an estimated π = 0.00212 diversity index. A clone containing the CesA2 gene was identified through a selection from a BAC library generated in the scope of the Genolyptus Project. This clone gives the prospect for the development of a minute characterization of this gene structure in Eucalyptus. Additionally, concerning the CesA3 gene, the sequencing of 32 individuals allowed for the formation of a 770bp contig with a π = 0.00185 diversity index and detection of nine polymorphic loci distributed in intron and exon regions and at the 3’-UTR of the gene. The analysis of the extension of linkage disequilibrium in the CesA3 gene suggests that SNPs tend to be in strong linkage disequilibrium at a distance of approximately 600bp. The knowledge of the position of the SNPs in the genes CesA2 and CesA3 makes possible the use of these markers in future studies of genetic mapping. The lack of non-synonymous SNPs in exon regions ensures that cellulose is in fact a very important polymer for plant survival. Hence its synthesis machinery presents highly conserved characteristics and so mutations in regions with effective transcription tend mostly to be deleterious and therefore would not be fixed. Moreover, the analysis of CesA gene expression in different species of Eucalyptus, was made from two boardings: “Digital Differential Display”, from different libraries of ESTs and microarrays, optimized in the scope of the Genolyptus project. The analysis with data of microarrays showed less sensible in the detention of the distinguishing expression, probably had to the calls “crossed relations”. / A celulose é um dos biopolímeros mais importantes do planeta, sendo também o mais abundante, e sem dúvida uma característica chave na história evolutiva das plantas. Contudo, sua biossíntese e regulação ainda não são bem compreendidas, embora avanços importantes tenham ocorrido nos últimos anos, sobretudo na identificação de genes e grupos de genes co-expressos para a formação de celulose na parede celular primária e secundária de vegetais. Além de sua relevância biológica, a celulose possui uma grande importância econômica no Brasil e no mundo, com destaque para a produção de celulose e papel a partir de Eucalyptus. Para garantir os elevados níveis de produtividade e competitividade no mercado internacional, grandes investimentos têm sido realizados pelo setor florestal, destacando-se o Projeto Genolyptus – Rede Brasileira de Pesquisa do Genoma de Eucalyptus, fruto de um esforço de empresas do setor de produção de celulose e papel, e de diversas instituições públicas de pesquisa, que têm, dentre outros objetivos, o intuito de identificar e caracterizar genes envolvidos na formação da madeira, para, no futuro, usar essa informação no melhoramento genético do Eucalyptus. Nesse contexto, este trabalho foi desenvolvido com o objetivo de realizar uma caracterização preliminar de um gene de celulose sintase em Eucalyptus, que está relacionado à síntese da parede celular secundária, sendo ortólogo ao gene EgCesA2, de E. grandis, bem como estudar o desequilíbrio de ligação em outro gene de celulose sintase, ortólogo ao gene EgCesA3, em uma amostra de uma população natural de E. urophylla. Em relação ao gene CesA2, foi seqüenciada uma região exônica do gene, formada por 427pb, a partir de amostras de DNA de 12 indivíduos de diferentes espécies e regiões geográficas. Procedeu-se a uma análise de detecção de polimorfismo, e estimou-se a ocorrência de três SNPs sinônimos ao longo do contig. Foi estimado um índice de diversidade π= 0,00212. Foi feita também uma triagem em uma biblioteca de BAC, gerada no âmbito do Projeto Genolyptus, e foi identificado o clone que contém o gene CesA2, o que permitirá o desenvolvimento futuro de caracterização minuciosa da estrutura deste gene em Eucalyptus. Em relação ao gene CesA3, a partir do seqüenciamento de 32 indivíduos, formou-se um contig de 770pb, e foi encontrado um índice de diversidade π= 0,00185. Foi possível a detecção de nove locos polimórficos distribuídos em regiões intrônicas, exônicas, e de 3’-UTR do gene. A análise de extensão do desequilíbrio de ligação dentro do gene CesA3 sugere que os SNPs tendem a se encontrar em forte desequilíbrio a uma distância de aproximadamente 600pb. O conhecimento da posição dos SNPs nos genes CesA2 e CesA3 viabiliza a utilização destas marcas em futuros estudos de mapeamento genético. A existência de SNPs sinônimos nas regiões exônicas seqüenciadas corrobora com a idéia de que a celulose é um polímero muito importante à sobrevivência da planta, e, portanto, sua maquinaria de síntese apresenta características bastante conservadas, de modo que mutações em regiões efetivamente transcritas tenderiam a ser deletérias e não seriam fixadas. Além disso, foi feita uma análise da expressão gênica dos genes CesA em diferentes espécies de Eucalyptus, a partir de duas abordagens: a “Digital Differential Display”, a partir de diferente bibliotecas de ESTs e os microarrays, otimizados no âmbito do projeto Genolyptus. A análise com dados de microarrays revelou-se menos sensível na detecção da expressão diferencial, provavelmente devido às chamadas “relações cruzadas”.

<p>This thesis describes the application of multivariate methods in analyses of genomic DNA sequences, gene expression and protein synthesis, which represent each of the steps in the central dogma of biology. The recent finalisation of large sequencing projects has given us a definable core of genetic data and large-scale methods for the dynamic quantification of gene expression and protein synthesis. However, in order to gain meaningful knowledge from such data, appropriate data analysis methods must be applied.</p><p>The multivariate projection methods, principal component analysis (PCA) and partial least squares projection to latent structures (PLS), were used for clustering and multivariate calibration of data. By combining results from these and other statistical methods with interactive visualisation, valuable information was extracted and further interpreted.</p><p>We analysed genomic sequences by combining multivariate statistics with cytological observations and full genome annotations. All oligomers of di- (16), tri- (64), tetra- (256), penta- (1024) and hexa-mers (4096) of DNA were separately counted and normalised and their distributions in the chromosomes of three Drosophila genomes were studied by using PCA. Using this strategy sequence signatures responsible for the differentiation of chromosomal elements were identified and related to previously defined biological features. We also developed a tool, which has been made publicly available, to interactively analyse single nucleotide polymorphism data and to visualise annotations and linkage disequilibrium.</p><p>PLS was used to investigate the relationships between weather factors and gene expression in field-grown aspen leaves. By interpreting PLS models it was possible to predict if genes were mainly environmentally or developmentally regulated. Based on a PCA model calculated from seasonal gene expression profiles, different phases of the growing season were identified as different clusters. In addition, a publicly available dataset with gene expression values for 7070 genes was analysed by PLS to classify tumour types. All samples in a training set and an external test set were correctly classified. For the interpretation of these results a method was applied to obtain a cut-off value for deciding which genes could be of interest for further studies.</p><p>Potential biomarkers for the efficacy of radiation treatment of brain tumours were identified by combining quantification of protein profiles by SELDI-MS-TOF with multivariate analysis using PCA and PLS. We were also able to differentiate brain tumours from normal brain tissue based on protein profiles, and observed that radiation treatment slows down the development of tumours at a molecular level.</p><p>By applying a multivariate approach for the analysis of biological data information was extracted that would be impossible or very difficult to acquire with traditional methods. The next step in a systems biology approach will be to perform a combined analysis in order to elucidate how the different levels of information are linked together to form a regulatory network.</p>

This thesis describes the application of multivariate methods in analyses of genomic DNA sequences, gene expression and protein synthesis, which represent each of the steps in the central dogma of biology. The recent finalisation of large sequencing projects has given us a definable core of genetic data and large-scale methods for the dynamic quantification of gene expression and protein synthesis. However, in order to gain meaningful knowledge from such data, appropriate data analysis methods must be applied. The multivariate projection methods, principal component analysis (PCA) and partial least squares projection to latent structures (PLS), were used for clustering and multivariate calibration of data. By combining results from these and other statistical methods with interactive visualisation, valuable information was extracted and further interpreted. We analysed genomic sequences by combining multivariate statistics with cytological observations and full genome annotations. All oligomers of di- (16), tri- (64), tetra- (256), penta- (1024) and hexa-mers (4096) of DNA were separately counted and normalised and their distributions in the chromosomes of three Drosophila genomes were studied by using PCA. Using this strategy sequence signatures responsible for the differentiation of chromosomal elements were identified and related to previously defined biological features. We also developed a tool, which has been made publicly available, to interactively analyse single nucleotide polymorphism data and to visualise annotations and linkage disequilibrium. PLS was used to investigate the relationships between weather factors and gene expression in field-grown aspen leaves. By interpreting PLS models it was possible to predict if genes were mainly environmentally or developmentally regulated. Based on a PCA model calculated from seasonal gene expression profiles, different phases of the growing season were identified as different clusters. In addition, a publicly available dataset with gene expression values for 7070 genes was analysed by PLS to classify tumour types. All samples in a training set and an external test set were correctly classified. For the interpretation of these results a method was applied to obtain a cut-off value for deciding which genes could be of interest for further studies. Potential biomarkers for the efficacy of radiation treatment of brain tumours were identified by combining quantification of protein profiles by SELDI-MS-TOF with multivariate analysis using PCA and PLS. We were also able to differentiate brain tumours from normal brain tissue based on protein profiles, and observed that radiation treatment slows down the development of tumours at a molecular level. By applying a multivariate approach for the analysis of biological data information was extracted that would be impossible or very difficult to acquire with traditional methods. The next step in a systems biology approach will be to perform a combined analysis in order to elucidate how the different levels of information are linked together to form a regulatory network.

Some dairy breeds have too few animals genotyped for within breed genomic selection to be carried out with sufficient accuracy. As such, the level of linkage disequilibrium within each breed as well as consistency of gametic phase across breeds was studied. High correlations of phase (>0.9) were found between all breed pairs at this same SNP density. The efficacy of imputing animals genotyped on lower density (6k and 50k) panels was then explored in order to increase the size of the reference population with 777k genotypes in a cost-effective manner. These results showed high accuracies (>0.92) in all imputation scenarios studies, using both a within breed and a multi-breed reference population for imputation. It was concluded that given the results of both of these studies, pooling breeds into a common reference population for genomic selection should be a viable option for accurate genomic selection in breeds with few genotyped individuals. / NSERC, USDA, CDN, DairyGen, Ayrshire Canada, Guernsey Canada, Semex, L'Alliance Boviteq Inc.