No description available.

The aetiology and pathogenesis of primary open angle glaucoma (POAG), the second most common cause of irreversible visual loss in the United Kingdom, remains a conundrum for contemporary ophthalmology. Evidence suggests that glaucoma is a complex disorder, where multiple genes interact with each other and with factors in the environment. However, the aetiological heterogeneity of glaucoma coupled with its varied clinical presentation and course has made the study of glaucoma genes problematic. We established the Orcades Eye Study, a cross sectional family based genetic study, to explore the inheritance of primary open angle glaucoma (POAG). As POAG is a disease of late onset and low prevalence, rather than study disease per se we chose to study quantitative traits (QTs) related to POAG, in an isolated population in the northern Scottish archipelago of Orkney. A number of factors in this population, including reduced genetic heterogeneity and more homogenous environmental effects, confer certain advantages over more admixed urban populations in complex disease gene mapping. Preliminary analysis of the procured quantitative trait data (n=256) has demonstrated that the values obtained for the POAG related QTs of intraocular pressure (IOP), central corneal thickness and a number of optic disc parameters including optic cup area, disc area, retinal nerve fiber thickness, vertical cup to disc ratio and peripapillary atrophy are not dissimilar to other published White Caucasian populations. We also found that intraocular pressure shows an increase with age and is influenced by central corneal thickness but found no relationship between IOP and gender or IOP and other ocular biometric variables including optic nerve head parameters and refractive components. Neither central corneal thickness nor optic nerve head parameters had a statistically significant relationship to age, gender or other tested ocular biometric parameters. These findings are clinically important as these factors should be taken into consideration when evaluating intraocular pressure and other ocular biometric traits in the investigation of glaucoma and other ocular diseases in the population of Orkney. Data collection is ongoing, and with time, an increased sample size and a meaningful genetic analysis, the Orcades Eye Study will hopefully identify genes and regions of the genome associated with primary open angle glaucoma susceptibility in the Scottish Population Isolate of Orkney. To our knowledge, the only other population based study which has investigated as large a number of glaucoma related QTs is the Beijing Eye Study.

Most human traits are influenced by a combination of genetic and environmental effects. Heritability expresses the proportion of trait variance that can be explained by genetic factors, and the 1980s heralded the beginning of studies that aimed to pinpoint genetic loci that contribute to trait variation, also known as quantitative trait loci (QTLs). Subsequently, the availability of cheap, high-resolution genotyping chips ushered in the era of genome-wide association studies (GWAS). These genetic studies have discovered many associations between single-nucleotide polymorphisms (SNPs) and complex traits, but these associations do not explain the genetic component of these traits entirely. This is known as the ‘missing heritability’ problem. Within this thesis, 40 medically-relevant human complex traits are studied in order to identify new QTLs. These traits include eye biometric traits, blood biochemical traits and anthropometric traits measured in approximately 28,000 individuals belonging to family-based samples from the general Scottish population (the Generation Scotland study) or from population isolates from Croatian (Korčula, Vis) or Scottish (Shetland, Orkney) islands. These individuals had been genotyped using commercially-available arrays, and unobserved genotypes were imputed using the Haplotype Reference Consortium (HRC) dataset. In parallel to standard GWAS, these traits are analysed using two other statistical genetics approaches: variance component linkage analysis and regional heritability (RH) mapping. Each study is analysed separately, in order to detect study-specific genetic effects that may not generalise across populations. At the same time, because most traits are available in several studies, this also enables meta-analysis, which boosts the power of discovery and can reveal cross-study genetic effects. These methods are a priori complementary to each other, exploiting different aspects of human genetic variation, such as the segregation of variants within families (identity by descent, IBD), or the presence of the same variant throughout the general population (identity by state, IBS). The strengths and weaknesses of these methods are systematically assessed by applying them to real and simulated datasets.

A quantitative trait locus (QTL) is the location of a gene that affects a trait that is measured on a quantitative (linear) scale. Many important agricultural traits such as weight gain, milk fat content and intramuscular fat in cattle are quantitative traits. There is a need to integrate genomic sequence data with QTL data and to develop an analytical tool to visualize the data. Without integration, application of this data to agricultural enterprise productivity will be slow and inefficient. My thesis presents a web-accessible tool called the Bovine QTL Viewer developed to solve this problem. It consists of an integrated database of bovine QTL and the QTL viewer to view the QTL and their relative chromosomal position. This tool generates dynamic and interactive images and supports research in the field of genomics. For this tool, the data is modeled and the QTL viewer is developed based on the requirements and feedback of experts in the field of bovine genomics.

<p>An unresolved problem in evolutionary biology is the nature of forces that maintain standing variation for quantitative traits. In this study we take advantage of newly developed genomic resources to understand how variation is maintained for flower size and fitness components in a natural population of annual Mimulus guttatus in the Oregon Cascades. Extensive inbreeding depression has been documented in this population for fertility and viability (Willis 1999 a,b), while previous biometric experiments have demonstrated that some of the floral variation in this site is due to common alleles perhaps maintained by balancing selection (Kelly and Willis 2001, Kelly 2003). Detailed comparison of the genetic architecture of these two categories of traits can clarify the relative contributions of mutation versus selection in maintaining trait variation within populations as well as the relevance of standing variation for trait diversification. </p><p>We present here the results from a large scale effort to dissect variation for flower size and a suite of genetically correlated traits. In 3 independent F2 mapping populations we mapped QTLs for floral morphology (flower width and length, pistil length, and stamen length), flowering time, and leaf size. We also mapped segregation distortion loci and QTLs for fertility components (pollen viability and seed set) that exhibit inbreeding depression. We compare the genetic architecture of these two sets of traits and find clear differences. Morphological traits and flowering time are polygenic and QTLs are generally additive. In contrast, deleterious QTLs associated with segregation distortion or fertility are partially recessive and include major QTLs. There is also little co-localization between morphological/flowering time and fertility QTLs. The analysis suggests that the genetic basis of segregating variation in morphology is fundamentally different from traits exhibiting inbreeding depression. Further, there is considerable variation in the extant of pleiotropy exhibited by QTLs for morphological traits as well as flowering time and we report that epistasis contributes to the standing variation for these traits. The analysis suggests that the standing variation is relevant for trait diversification and that the variation in floral allometry, plant form, and life history observed in the guttatus species complex could have readily evolved from the standing variation.</p> / Dissertation

A quantitative trait locus (QTL) is the location of a gene that affects a trait that is measured on a quantitative (linear) scale. Many important agricultural traits such as weight gain, milk fat content and intramuscular fat in cattle are quantitative traits. There is a need to integrate genomic sequence data with QTL data and to develop an analytical tool to visualize the data. Without integration, application of this data to agricultural enterprise productivity will be slow and inefficient. My thesis presents a web-accessible tool called the Bovine QTL Viewer developed to solve this problem. It consists of an integrated database of bovine QTL and the QTL viewer to view the QTL and their relative chromosomal position. This tool generates dynamic and interactive images and supports research in the field of genomics. For this tool, the data is modeled and the QTL viewer is developed based on the requirements and feedback of experts in the field of bovine genomics.

No description available.

Chicken is a major protein source and intensively selected for economically important traits by humans. As such, this generated a huge range of phenotypes that representing a diverse spectrum of genetic variation. Understanding the functional basis of the genetic variants that underlie these traits, however, remains a formidable endeavour particularly for complex traits. Nonetheless, molecular phenotyping of an organism from sequenced data is doable with the advances in bioinformatics analysis and unparalleled surveys of genome wide genetic variants. This provides the opportunity to gain insights into the genome architecture and assists in identifying chromosomal regions underlying selection through a “sequences to consequences” approach. Combining a whole genome re-sequencing (WGS) approach with the knowledge of selection history, this thesis aimed to study the chromosomal regions and genetic variants underlying traits of interest in various selected chicken populations. To achieve this, genetic (quantitative and population genetics), genomic and bioinformatics approaches were employed and integrated to investigate the genome wide selection signatures in a number of different lines of chicken selected for different complex traits. This includes analysing: (i) divergently selected broilers for fatness traits (Chapter 2), (ii) a closed population of layer chickens (Chapter 3), (iii) selection signatures unique to broiler or layer chickens (Chapter 4) and (iv) selection signatures in colony stimulating factor 1 (CSF1) associated with gene expression differences in broiler and layer populations (Chapter 5). Candidate genes and nucleotides underlying potential selection regions were identified, and attempts were made to further elucidate the potential interplay between genes and the biological pathways involved in regulating traits in these selected chicken lines. Incorporating integrative approaches, variants within selection signatures were annotated to provide further evidence of their functional consequences. Overall, non-coding regions were enriched in selection signatures implied that causative variants may have regulatory roles. Capitalising on the millions of genetic variants discovered from WGS, chromosomal regions subject to selection were detected using a number of population genetics statistics. In broiler chicken lines divergently selected for very low-density plasma lipoprotein (VLDL) (Chapter 2), incorporating signatures of selection helped to improve the resolution of previously mapped quantitative traits loci (QTL) intervals. This research demonstrated that the integration of the analysis of selection signatures with functional annotation of genetic variants enabled refinement and characterisation of the QTL for fatness traits. In a closed population of brown leghorn layers (Chapter 3), evidence of selection signatures was found through Tajima’s D analysis. The analysis unravelled selection signatures encoding genes involved in numerous pathways and genes having key roles such as in behaviour, including feather pecking. Combining population differentiation statistic (FST) and Tajima’s D, a number of regions subject to divergent selection between broilers and white egg layers were identified (Chapter 4). Selection signatures were found to harbour mutations involved in cellular and tissue development, including genes having important roles in growth, fatness, egg shell strength and muscle development. These regions and the overlapping genes thereby may be potentially contributing to the different phenotypic variations observed between broilers and layers. In Chapter 5, a revised gene model for colony stimulating factor 1 (CSF1) showing complex pattern of alternate transcripts was predicted from transcriptome analysis of RNA isolated from 21 different tissues. In parallel, selection signatures analysis with the FST statistic, identified selection signatures that differentiate broilers to white egg layers (3 regions) or brown egg layers to white egg layers (4 regions). All these selection signatures were located within non-coding regions, indicating potential divergent selection of CSF1 within regulatory regions. Overall, the results presented in this thesis using the “sequences to consequences” approach, link several genomic regions and genes to phenotypic variation in domesticated chicken lines. The work reported here serves as a foundation for further study to decipher the relationship between “genotype and phenotype” and its functional consequences due to selection.

La variabilité phénotypique existante au sein d’une population est d’une importance cruciale ; elle permet l’adaptation à de nouvelles conditions par la sélection naturelle de traits bénéfiques. La variabilité phénotypique est le résultat du polymorphisme génétique de chaque individu, couplé à l’influence de divers facteurs environnementaux. Ces travaux ont pour objectif d’élucider quels sont les facteurs génétiques responsables de la variabilité phénotypique de chaque individu afin de comprendre comment celle-ci évolue de génération en génération et peut s’accentuer au-delà des prédispositions parentales. Finalement, les résultats obtenus seront utilisés pour prédire un phénotype à partir d’un génotype inconnu. Nous avons utilisé des techniques de phénomique et de génomique de haut débit pour décomposer avec une précision inédite la variabilité phénotypique d’une large population de souches diploïdes de Saccharomyces cerevisiae. Le génotype exact de plus de 7000 souches uniques a ainsi été obtenu via le croisement et le séquençage de souches haploïdes distinctes. Nous avons mesuré la capacité de croissance de ces souches et identifié les composants génétiques influant sur ce trait. De plus, nous avons identifié des « loci de caractères quantitatifs » additifs et non-additifs, et étudié la fréquence du phénomène d’hétérosis et ses mécanismes. Enfin, en utilisant les données phénotypiques et génotypiques de la même population de levures, nous avons pu prédire les traits de chaque individu avec une presque parfaite exactitude. Ces travaux ont ainsi permis d’identifier avec précision les facteurs génétiques modulant la variation phénotypique d’une population diploïde, et de prédire un trait à partir du génotype et de l’ensemble des données phénotypiques. En plus de ce projet, nous travaillons aussi sur l’identification des bases génétiques à l’origine de la non-viabilité des gamètes, ainsi que sur la compréhension des caractères complexes chez des souches hybrides intra-espèce. De par l’étude de 9000 gamètes séquencés issus de six hybrides différents, nous avons pour objectif de caractériser leur profil de recombinaison et d’observer quelle est l’influence du fond génétique sur ce dernier. De plus, nous avons caractérisé la capacité de croissance de ces gamètes dans neuf conditions environnementales différentes et nous prévoyons de disséquer l’architecture génétique de ces traits dans différents fonds génétiques. / The phenotypic variation between individuals in a population is of crucial importance. It allows populations to evolve to novel conditions by the natural selection of beneficial traits. Variation in traits can be caused by genetic or environmental factors. This work endeavors to study the genetic factors that underlie phenotypic variation in order to understand how variation can be created from one generation to the next; to know what genetic mechanisms are most prominent; to learn how variation can extend beyond the parents; and finally, to use this in order to predict phenotypes of unknown genetic constellations. We used large scale phenomics and genomics to give an unprecedented decomposition of the phenotypic variation in a large population of diploid Saccharomyces cerevisiae strains. Constructing phased outbred lines by large scale crosses of sequenced haploid strains allowed us to infer the genetic makeup of more than 7,000 colonies. We measured the growth of these strains and decomposed the phenotypic variation into its genetic components. In addition, we mapped additive and nonadditive quantitative trait loci, we investigated the occurrence of heterosis and its genetic basis, and using the same populations we used phenotypic and genetic data to predict traits with near perfect accuracy. By using the phased outbred line approach, we succeeded in giving a conclusive account of what genetic factors define phenotypic variation in a diploid population, and in accurately predicting phenotypes from genetic and phenotypic data. Beyond the phased outbred line project, I am currently investigating the genetic basis of gamete inviability and complex traits in intraspecies yeast hybrids. Using 9,000 sequenced gametes from six different hybrids we aim to characterize their recombination landscape and how the genetic background influences it. Furthermore, we have phenotyped these gametes in nine conditions and will dissect the genetic architecture of these traits across multiple genomic backgrounds.

Submitted by DANILLA CRISTINA LEMOS SOUZA null (danillacristina@ig.com.br) on 2017-03-23T12:18:23Z No. of bitstreams: 1 TESE - Danilla Souza com ficha.pdf: 2474993 bytes, checksum: 4fede4ee91d0e6d92b69f3cdf397643c (MD5) / Approved for entry into archive by Luiz Galeffi (luizgaleffi@gmail.com) on 2017-03-23T14:55:55Z (GMT) No. of bitstreams: 1 souza_dcl_dr_bot.pdf: 2474993 bytes, checksum: 4fede4ee91d0e6d92b69f3cdf397643c (MD5) / Made available in DSpace on 2017-03-23T14:55:55Z (GMT). No. of bitstreams: 1 souza_dcl_dr_bot.pdf: 2474993 bytes, checksum: 4fede4ee91d0e6d92b69f3cdf397643c (MD5) Previous issue date: 2017-02-16 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Myracrodruon urundeuva (Anacardiaceae) é uma espécie arbórea de ampla distribuição geográfica. Por possuir madeira de reconhecido valor econômico, associada à alta taxa de fragmentação dos seus habitats, encontra-se ameaçada de extinção. Com o intuito de manter a variabilidade genética existente das populações fragmentadas e reduzir perdas na base genética da espécie, sementes de polinização aberta de M. urundeuva foram coletadas em diferentes regiões, no Brasil, para formação do banco de conservação ex situ da Faculdade de Engenharia de Ilha Solteira, em Selvíria-MS. Esse trabalho foi realizado com o objetivo de caracterizar o sistema de reprodução e estimar parâmetros genéticos populacionais em progênies de M. urundeuva, procedentes de diferentes biomas brasileiros, por meio de caracteres quantitativos de crescimento e marcadores moleculares do tipo microssatélites. Os caracteres altura, diâmetro a altura do peito (DAP), diâmetro médio de copa e sobrevivência (SOB) foram utilizados para avaliar cinco populações: Aquidauana-MS, Selvíria-MS, Itarumã-GO, Paulo de Faria-SP e Seridó-RN. Os valores altos a medianos observados para SOB (96,4% - 70,8%) indicam boa adaptação das populações de M. urundeuva e potencial para uso em reflorestamentos. As estimativas do coeficiente de variação genética oscilaram de 3% a 24,6%, em nível de indivíduo, e de 1,5% a 12,3%, entre progênies, com os maiores valores obtidos para o DAP da população de Seridó. As herdabilidades individuais variaram de moderada (0,41) a baixa (0,01) para os caracteres apresentados. Empregando-se o valor genético dos indivíduos, o DAP foi utilizado para estimar ganhos genéticos na seleção de indivíduos dentro de progênies, sendo a população de Itarumã a mais indicada ao melhoramento genético, no referido ano de avaliação destas populações (população de Itarumã aos 11 anos de idade). Para análise molecular, 20 locos microssatélites foram desenvolvidos, a partir do sequenciamento de nova geração (MiSeq Sequencing System, Illumina), e seis desses foram utilizados para caracterizar as populações de Aquidauana, Itarumã, Paulo de Faria e Seridó (1.224 indivíduos). O número total de alelos (215), o número de diferentes alelos (67) e os valores de heterozigosidades observados demonstraram que estas populações ainda conservam índices de diversidade genética consideravelmente altos. Foi detectada alta diferenciação genética entre as populações (33%), relacionada, em partes, à distância que as separam; e foi confirmado que a espécie dioica M. urundeuva reproduz-se por cruzamento. Estes cruzamentos não são aleatórios nas populações, com aumento do grau de parentesco nas populações que sofreram forte pressão antrópica. Os coeficientes de coancestria dentro de progênies foram superiores ao esperado em progênies de meios-irmãos (0,125), portanto, estas progênies são constituídas também de irmãos-completos. Visando à utilização em reflorestamentos, estratégias de coleta de sementes devem ser adotadas, de modo a evitar a obtenção de sementes advindas de cruzamentos correlacionados ou endogâmicos, estabelecendo-se o valor mínimo de coleta em 55 árvores matrizes, em cada população, de modo a garantir um tamanho efetivo de população de 150. As informações obtidas com este estudo são úteis para fins de conservação e melhoramento genético da espécie, como também para seleção de matrizes potenciais para recuperação ambiental. / Myracrodruon urundeuva (Anacardiaceae) is a tree species with a wide geographic distribution. Because it has wood of recognized economic value, associated with the high rate of fragmentation of its habitats, it is threatened with extinction. In order to maintain the existing genetic variability of the fragmented populations and reduce losses in the genetic base of the species, M. urundeuva seeds were collected in different regions in Brazil for the formation of the ex situ conservation bank of the Faculty of Engineering of Ilha Solteira (FEIS/UNESP), in Selvíria-MS. This work was conducted with the aims to characterize the mating system and estimate population genetic parameters in M. urundeuva offsprings from different Brazilian biomes, using quantitative growth traits and molecular markers of the microsatellite type. The height, diameter at breast height (DBH), mean crown diameter and survival were used to evaluate five populations: Aquidauana-MS, Selvíria-MS, Itarumã-GO, Paulo de Faria -SP and Seridó-RN. The values high to median observed for survival (96.4% - 70.8%) indicate good adaptation of populations of M. urundeuva and potential for use in reforestation. Estimates of the coefficient of genetic variation ranged from 3% to 24.6%, at the individual level, and from 1.5% to 12.3%, among progenies, with the highest values obtained for the DBH of the Seridó population. The individual heritabilities ranged from moderate (0.41) to low (0.01) for the characters. Using the genetic value of the individuals, DBH was used to estimate genetic gains in the selection of individuals within progenies, and the Itarumã population being the most indicated for breeding, in the said year of evaluation of these populations (Itarumã population at 11 years old). For molecular analysis, 20 microsatellite loci were developed from the new generation sequencing (MiSeq Sequencing System, Illumina), and six of these were used to characterize the populations of Aquidauana, Itarumã, Paulo de Faria and Seridó (1,224 individuals).The total number of alleles (215), the number of different alleles (67) and the observed heterozygosity values demonstrated that these populations still retain considerably high genetic diversity indices. High genetic differentiation was detected among populations (33%), related, in part, the distance separating them; and it was observed that the species dioica M. urundeuva is reproduced by mating. These matings are not random in populations, with increased degree of relationship in populations with strong anthropic pressure. The coancestry coefficients within offspring were higher than expected in half-sibs offsprings (0.125), so these offsprings are also composed of full-sibs. Aiming at the use in reforestation, seed collection strategies should be adopted, in order to avoid obtaining seeds produced from related or inbred matings, establishing the minimum collection amount in 55 seed trees, in each population, so to ensure an effective population size of 150. The informations obtained from this study are useful for the purpose of conservation and breeding of the species, but also for selection of potential matrices for environmental recovery. / FAPESP: 2013/24503-1