The publication of a draft equine genome sequence and the release by Illumina of a 50,000 marker single-nucleotide polymorphism (SNP) genotyping chip has provided equine researchers with the opportunity to use new approaches to study the relationships between genotype and phenotype. In particular, it is hoped that the use of high-density markers applied to population samples will enable progress to be made with regard to more complex diseases. The first objective of this thesis is to explore the potential for the equine SNP chip to enable such studies to be performed in the horse. The second objective is to investigate the genetic background of osteochondrosis (OC) in the horse. These objectives have been tackled using 348 Thoroughbreds from the US, divided into cases and controls, and a further 836 UK Thoroughbreds, the majority with no phenotype data. All horses had been genotyped with the Illumina Equine SNP50 BeadChip. Linkage disequilibrium (LD) is the non-random association of alleles at neighbouring loci. The reliance of many genomic methodologies on LD between neutral markers and causal variants makes it an important characteristic of genome structure. In this thesis, the genomic data has been used to study the extent of LD in the Thoroughbred and the results considered in terms of genome coverage. Results suggest that the SNP chip offers good coverage of the genome. Published theoretical relationships between LD and historical effective population size (Ne) were exploited to enable accuracy predictions for genome-wide evaluation (GWE) to be made. A subsequent in-depth exploration of this theory cast some doubt on the reliability of this approach in the estimation of Ne, but the general conclusion that the Thoroughbred population has a small Ne which should enable GWE to be carried out efficiently in this population, remains valid. In the course of these studies, possible errors embedded within the current sequence assembly were identified using empirical approaches. Osteochondrosis is a developmental orthopaedic disease which affects the joints of young horses. Osteochondrosis is considered multifactorial in origin with a variety of environmental factors and heredity having been implicated. In this thesis, a genome-wide association study was carried out to identify quantitative trait loci (QTL) associated with OC. A single SNP was found to be significantly associated with OC. The low heritability of OC combined with the apparent lack of major QTL suggests GWE as an alternative approach to tackle this disease. A GWE analysis was carried out on the same dataset but the resulting genomic breeding values had no predictive ability for OC status. This, combined with the small number of significant QTL, indicates a lack of power which could be addressed in the future by increasing sample size. An alternative to genotyping more horses for the 50K SNP chip would be to use a low-density SNP panel and impute remaining genotypes. The final chapter of this thesis examines the feasibility of this approach in the Thoroughbred. Results suggest that genotyping only a subset of samples at high density and the remainder at lower density could be an effective strategy to enable greater progress to be made in the arena of equine genomics. Finally, this thesis provides an outlook on the future for genomics in the horse.

O mapeamento genético e a genética funcional de doenças são de grande importância na pesquisa médica e genômica. Para estas finalidades o estudo de associação entre fatores de risco genéticos e doença tem ganhado destaque na literatura. Neste trabalho disserta-se sobre a análise de associação aplicada ao mapeamento genético de doenças, caracterizando diferentes possibilidades de planejamentos experimentais e de utilização de modelos estatísticos de análise de dados. As formalizações estatísticas, como o tipo de delineamento experimental, a inclusão ou não de dados familiares, bem como a escolha do método estatístico de análise, que são decisivos na avaliação do poder dos testes obtidos e na sua aplicabilidade ao mapeamento genético, também são discutidas. Além disso, considera-se a análise de associação por meio de modelos de regressão logística em que, as análises de dados genéticos são abordadas via dados no nível genotípico e cromossômico. Finalmente, os conceitos supracitados são aplicados a conjuntos de dados reais, fornecidos pelo Laboratório de Cardiologia e Genética Molecular do InCor/USP, com o objetivo de ilustrar o problema teórico tratado e motivar a aplicação das metodologias estatísticas envolvidas. / The genetic mapping and functional genetics have great importance in the genomics research. In order to conduct these researches the study of the association between genetic risk factors and disease has been becoming an important role in the literature. In this work we consider the association analyses applied to the genetic diseases mapping, charactering different possibilities of experimental designs and the use of statistical models to analyze data sets. The statistical concepts, as the kind of experimental design, the inclusion of familiar records or not, as well as the choice of the statistical analyze method, which are very important to the evaluation of the power of the tests obtained and to their applicability in the genetic mapping, are also discussed. Furthermore, we consider the association analysis at person level and chromosome data set. Finally, the latter concepts are applied to a real data set, provided by the Molecular Genetic and Cardiology Laboratory of InCor/USP, in order to illustrate the theoretical problem treated in this work and to motive the use of the involved statistical methodologies.

Made available in DSpace on 2017-07-10T17:37:17Z (GMT). No. of bitstreams: 1 Elcio_Friske.pdf: 2134254 bytes, checksum: a68baa9abb11f51692fe7500a517561f (MD5) Previous issue date: 2016-02-29 / Fundação Araucária / The aim of this work was to evaluate the genetic diversity and map genomic regions associated with grains maturation in common corn lineages. The phenotypic attributes of 81 elite inbred lines of corn were assessed in field experiment implanted in square lattice design with three repetitions. The variance and multivariate analysis were carried out considering complete randomized blocks due to its equivalence with the estimation for the lattice efficiency. For the mapping by linkage disequilibrium, 72 elite inbred lines have been genotyped for SNP markers at platform 650K (Affymetrix®) and associated with the genotypic values of the traits related to maturation: number of days for the male flowering (DFM) and female (DFF), and the grain moisture loss, determined by the area below the moisture curve (AACUM). The results of the variance analysis pointed out the existence of genetic diversity in the germplasm for all the assessed traits, detecting a wide variability for DFM, DFF and AACUM. Weak genetic correlations between yield and maturation components indicated the possibility of selection for earliness without compromising the grain yield. The genetic diversity quantified by the distances of Mahalanobis enabled the suggestion of hybrid combinations of higher heterotic effect for earliness and grain yield. There were similarities in the Tocher and UPGMA grouping, which were efficient to classify the genetic variability. By the mixed linear model (MLM) it was possible to detect associations among days for male and female flourishing with SNP markers in all chromosomes, with predominance of chromosomes 1 and 3 and for the loss of moisture in the chromosomes 5 and 6. With of multiple regression analysis of stepwise for DFM, DFF and AACUM, the complete models explained 79%, 93% and 56% of the variation for the genotypic values, respectively, being found predominantly significant markers in the chromosomes 1 and 3. The detection of similar and also different genomic regions for these traits, which are highly correlated, makes possible to raise the hypothesis of the importance of the genetic linkage and pleiotropy to explain the maturation of grains in corn inbred lines. The results obtained are promising and the genomic regions associated with DFM, DFF and AACUM, will be evaluated in validation experiments, which will be useful in selection programs of genotypes with the maturity sought by the breeder / O trabalho teve como objetivos avaliar a diversidade genética e mapear regiões genômicas associadas com maturação de grãos em linhagens de milho comum. Os atributos fenotípicos de 81 linhagens elites de milho foram avaliados em experimento de campo implantado em delineamento de látice quadrado com três repetições. Procedeu-se a análise de variância e multivariada considerando blocos completos casualizados devido a sua equivalência com a estimação para eficiência do látice. Para o mapeamento por desequilíbrio de ligação, 72 linhagens elites foram genotipadas para marcadores SNP na plataforma 650K (Affymetrix®) e associados aos valores genotípicos dos caracteres relacionados à maturação: número de dias para o florescimento masculino (DFM) e feminino (DFF), e perda de umidade dos grãos, determinada pela área abaixo da curva de umidade (AACUM). Os resultados da análise de variância indicaram a existência de diversidade genética no germoplasma para todos os caracteres avaliados, detectando-se ampla variabilidade para DFM, DFF e AACUM. Correlações genéticas fracas entre os componentes de rendimento e de maturação indicaram a possibilidade de seleção para precocidade sem comprometer a produtividade. A diversidade genética quantificada pelas distâncias de Mahalanobis permitiu sugerir combinações hibridas de maior efeito heterótico para precocidade e produtividade. Houve semelhanças no agrupamento de Tocher e UPGMA, que foram eficientes para classificar a variabilidade genética. Pelo modelo linear misto (MLM) foi possível detectar associações entre dias para o florescimento masculino e feminino com marcadores SNP em todos os cromossomos, com predominância nos cromossomos 1 e 3, e para perda de umidade nos cromossomos 5 e 6. Com a análise de regressão múltipla de stepwise para DFM, DFF e AACUM, os modelos completos explicaram 79%, 93% e 56% da variação para os valores genotípicos, respectivamente, encontrando-se predominantemente marcadores significativos nos cromossomos 1 e 3. A detecção de regiões genômicas semelhantes e também distintas para esses caracteres, que são altamente correlacionados, torna possível levantar a hipótese da importância de ligação gênica e de pleiotropia para explicar a maturação de grãos em linhagens de milho. Os resultados obtidos são promissores e as regiões genômicas associadas com DFM, DFF e AACUM, serão avaliadas em experimentos de validação, que poderão ser úteis em programa para seleção de genótipos com a maturidade buscada pelo melhorista

In this dissertation, the posterior probability of linkage (PPL) framework is extended to the analysis of case-control (CC) data and three new linkage disequilibrium (LD) statistics are introduced. These statistics measure the evidence for or against LD, rather than testing the null hypothesis of no LD, and they therefore avoid the need for multiple testing corrections. They are suitable not only for CC designs but also can be used in application to family data, ranging from trios to complex pedigrees, all under the same statistical framework, allowing for the unified analysis of these disparate data structures. They also provide the other core advantages of the PPL framework, including the use of sequential updating to accumulate LD evidence across potentially heterogeneous sets of subsets of data; parameterization in terms of a very general trait likelihood, which simultaneously considers dominant, recessive, and additive models; and a straightforward mechanism for modeling two-locus epistasis. Finally, being implemented within the PPL framework, the new statistics readily allow linkage information obtained from distinct data, to be incorporated into LD analyses in the form of a prior probability distribution. Performance of the proposed LD statistics is examined using simulated data. In addition, the effects of key modeling violations on performance are assessed. These statistics are also applied to a previously published type 1 diabetes (T1D) family dataset with a few candidate genes with previously reported weak associations, and another T1D CC dataset also previously published as a genome-wide association (GWA) study with some strong associations reported. The new LD statistics under the PPLD framework confirm most of the findings in the published work and also find some new SNPs suspected of being associated with T1D. Sequential updating between the family dataset and the CC dataset dramatically increased the association signal strength for a CTLA4 SNP genotyped in both studies. Linkage information gleaned from the family dataset is also combined into the LD analysis of the CC dataset to demonstrate the utility of this unique feature of the PPL framework, and specifically for the new LD statistics.

Variations in gene expression have long been hypothesised to be the major cause of individual differences. An initial focus of this research thesis is to elucidate the genetic regulatory architecture of gene expression. Expression quantitative trait locus (eQTL) mapping analyses have been performed on expression levels of over 22,000 mRNAs from three tissues of a panel of recombinant inbred mice. These analyses are "single-locus" where "linkage" (i.e. significant correlation) between an expression trait and a putative eQTL is considered independently of other loci. Major conclusions from these analyses are: 1. Gene expression is mainly influenced by genetic (sequence) variations that act in trans rather than in cis; 2. Subsets of genes are controlled by master regulators that influence multiple genes; 3. Gene expression is a polygenic trait with multiple regulators. Single-locus mapping analyses are not designed for detecting multiple regulators of gene expression, and so observation of multiple-linkages (i.e. one expression trait mapped to multiple eQTLs) formed the basis of the second objective of this research project: to investigate the relationship between multiple-linkages and genotype pattern-association. A locus-pair is said to have associated genotype patterns if they have similar inheritance pattern across a panel of individuals, and these are attributed to one of fours sources: 1. linkage disequilibrium between loci located on the same chromosome; 2. non-syntenic association; 3. random association; 4. un-associated. To understand the validity of multiple-linkages observed in single-locus mapping studies, a newly developed method, bqtl.twolocus, is applied to confirm two-locus effects for a total of 898 out of 1,233 multiple-linkages identified from the three studies mentioned above as well as from seven publicly available eQTL-mapping studies. Combining these results with information of genotype pattern-association, a subset of 478 multiple-linkages has been deduced for which there is high confidence to be real.

<p>Understanding the processes that shape the spatial distribution of genetic variation within species is central to the evolutionary study of diversification and demography. Neutral genetic variation reflects past demographic events as well as current demographic characteristics of populations, and the correct interpretation of genetic data requires that the relative impact of these forces can be identified. Details of breeding systems can affect the genetic structure through effects on effective migration rate or on effective population size. Restrictions in recombination rate lead to associations between neutral marker genes and genes under natural selection. Although the effects on genetic structure can be substantial, the process will often be difficult to tell apart from stochastic effects of history or genetic drift, which may suggest erroneous conclusions about demography.</p><p>In cyclically parthenogenetic freshwater invertebrates, which alternate between sexual and asexual reproduction, demographic fluctuations and reliance on diapausing eggs for dispersal enhances neutral genetic differentiation as well as effects of selection on associated genes. Although genetic founder effects are expected to be profound and long-lasting in these species, genetic hitch-hiking may reduce initial strong differentiation rapidly if better adapted genes are introduced by mutation or immigration. Fluctuating environmental conditions have been suggested to generate rapid shifts in the frequencies of clones during the asexual phase. In the presence of egg banks resting in sediments, genetic diversity is stabilised and the importance of migration for differentiation is reduced.</p><p>Studies of unstable and young populations of cyclically parthenogenetic <i>Daphnia pulex</i> showed substantial variation for important fitness traits, within as well as between populations, despite hypothesised recent founder effects. Neutral markers indicated genetic equilibrium, but changes in clonal composition during asexuality disrupted the genetic structure in a manner compatible with local adaptation and exclusion of immigrants. This illustrates that the forces affecting sexual progeny may be markedly different from those shaping the structure among asexual individuals.</p>

The first goal of the present work focuses on the need for different rationing methods of the The Global Change and Financial Transition (GFT) work- ing group at the Potsdam Institute for Climate Impact Research (PIK): I provide a toolbox which contains a variety of rationing methods to be ap- plied to micro-economic disequilibrium models of the lagom model family. This toolbox consists of well known rationing methods, and of rationing methods provided specifically for lagom. To ensure an easy application the toolbox is constructed in modular fashion. The second goal of the present work is to present a micro-economic labour market where heterogenous labour suppliers experience consecu- tive job opportunities and need to decide whether to apply for employ- ment. The labour suppliers are heterogenous with respect to their qualifi- cations and their beliefs about the application behaviour of their competi- tors. They learn simultaneously – in Bayesian fashion – about their individ- ual perceived probability to obtain employment conditional on application (PPE) by observing each others’ application behaviour over a cycle of job opportunities. / In vorliegender Arbeit beschäftige ich mich mit zwei Dingen. Zum einen entwickle ich eine Modellierungstoolbox, die verschiedene Rationierungs- methoden enthält. Diese Rationierungsmethoden sind entweder aus der Literatur bekannt, oder wurden speziell für die lagom Modellfamilie ent- wickelt. Zum anderen zeige ich, dass man mit Hilfe von Rationierungsmetho- den aus der Modellierungstoolbox einen fiktiven Arbeitsmarkt modellie- ren kann. Auf diesem agieren arbeitssuchende Agenten, die heterogen im Bezug auf ihre Qualifikation und ihre Vorstellungen über das Bewerbungs- verhalten ihrer Konkurrenten sind. Sie erfahren aufeinanderfolgende Job- angebote und beobachten das Bewerbungsverhalten ihrer Konkurrenten, um in Bayesianischer Weise über ihre individuelle Wahrscheinlichkeit eine Stelle zu erhalten zu lernen.

This thesis consists of four self-contained papers related to banking, credit markets and financial stability.    Paper [I] presents a credit market model and finds, using an agent based modeling approach, that credit crunches have a tendency to occur; even when credit markets are almost entirely transparent in the absence of external shocks. We find evidence supporting the asset deterioration hypothesis and results that emphasize the importance of accurate firm quality estimates. In addition, we find that an increase in the debt’s time to maturity, homogenous expected default rates and a conservative lending approach, reduces the probability of a credit crunch. Thus, our results suggest some up till now partially overlooked components contributing to the financial stability of an economy.     Paper [II] derives an econometric disequilibrium model for time series data. This is done by error correcting the supply of some good. The model separates between a continuously clearing market and a clearing market in the long-run such that we are able to obtain a novel test of clearing markets. We apply the model to the Swedish market for short-term business loans, and find that this market is characterized by a long-run nonmarket clearing equilibrium.    Paper [III] studies the risk-return profile of centralized and decentralized banks. We address the conditions that favor a particular lending regime while acknowledging the effects on lending and returns caused by the course of the business cycle. To analyze these issues, we develop a model which incorporates two stylized facts; (i) banks in which lendingdecisions are decentralized tend to have a lower cost associated with screening potential borrowers and (ii) decentralized decision-making may generate inefficient outcomes because of lack of coordination. Simulations are used to compare the two banking regimes. Among the results, it is found that even though a bank group where decisions are decentralizedmay end up with a portfolio of loans which is (relatively) poorly diversified between regions, the ability to effectively screen potential borrowers may nevertheless give a decentralized bank a lower overall risk in the lending portfolio than when decisions are centralized.    In Paper [IV], we argue that the practice used in the valuation of a portfolio of assets is important for the calculation of the Value at Risk. In particular, a seller seeking to liquidate a large portfolio may not face horizontal demand curves. We propose a partially new approach for incorporating this fact in the Value at Risk and Expected Shortfall measures and in an empirical illustration, we compare it to a competing approach. We find substantial differences.

Understanding the processes that shape the spatial distribution of genetic variation within species is central to the evolutionary study of diversification and demography. Neutral genetic variation reflects past demographic events as well as current demographic characteristics of populations, and the correct interpretation of genetic data requires that the relative impact of these forces can be identified. Details of breeding systems can affect the genetic structure through effects on effective migration rate or on effective population size. Restrictions in recombination rate lead to associations between neutral marker genes and genes under natural selection. Although the effects on genetic structure can be substantial, the process will often be difficult to tell apart from stochastic effects of history or genetic drift, which may suggest erroneous conclusions about demography. In cyclically parthenogenetic freshwater invertebrates, which alternate between sexual and asexual reproduction, demographic fluctuations and reliance on diapausing eggs for dispersal enhances neutral genetic differentiation as well as effects of selection on associated genes. Although genetic founder effects are expected to be profound and long-lasting in these species, genetic hitch-hiking may reduce initial strong differentiation rapidly if better adapted genes are introduced by mutation or immigration. Fluctuating environmental conditions have been suggested to generate rapid shifts in the frequencies of clones during the asexual phase. In the presence of egg banks resting in sediments, genetic diversity is stabilised and the importance of migration for differentiation is reduced. Studies of unstable and young populations of cyclically parthenogenetic Daphnia pulex showed substantial variation for important fitness traits, within as well as between populations, despite hypothesised recent founder effects. Neutral markers indicated genetic equilibrium, but changes in clonal composition during asexuality disrupted the genetic structure in a manner compatible with local adaptation and exclusion of immigrants. This illustrates that the forces affecting sexual progeny may be markedly different from those shaping the structure among asexual individuals.

To understand the factors that influence the spatio-temporal distribution of built space, and thus population in an urban area, play an extremely important role in our greater understanding of urban travel behaviour. Existing location of activity centres, especially home and work, strongly influences the short-term individual-level decisions such as mode of transportation, and long-term household-level decisions such as change in job and residential location. Conditions in the built space market also affect households’ and firms’ location and relocation decisions, and hence influence the general travel patterns in an urban area. This research addresses two very important, but at the same time, not very widely investigated dimensions that play a key role in the evolution of built space and population distribution: Markets and Decisions. A disequilibrium based microsimulation modelling framework is developed for the built space markets. This framework is then used to operationalize the Greater Toronto and Hamilton Area’s owner-occupied housing market within Integrated Land Use Transportation and Environment (ILUTE) modelling system. Simulation results captured heterogeneity in the transaction prices, due to type of dwellings and different market conditions, in a very disaggregate fashion. On the decisions side, this research first developed a generic multidimensional modelling framework that captures the behaviour of builders in terms of the supply of new built space. The where, when, how much, and what type of supply decisions were incorporated within a single framework. This modelling framework was then applied to estimate a model for the supply of new office space in the Greater Toronto Area (GTA). Estimation results indicated a risk taker behaviour on the builders’ part, while market conditions and supply of resources (labour, construction cost etc.) were also found to be important factors in decision making. In addition to that, this research also developed a comprehensive hedonic analysis for the asking rent of office space in the Greater Toronto Area. The effects of accessibility, quality, location, and market conditions on rent were explored. Data indicated a high degree of spatial heterogeneity and clustering effects. Spatial analysis techniques were incorporated within the hedonic framework to capture these effects. Estimation results indicated that access to transport infrastructure, distance from CBD, and vacancy rate were significant in explaining the variation in the rent.