Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell disorders with ineffective hematopoiesis. It is characterized by morphological dysplasia, peripheral cytopenias affecting one or more cell lineages and an increased risk of transformation into acute myeloid leukemia (AML). The early stages of MDS can be considered a premalignant disease. The pathogenesis of MDS has not been fully explained yet, but due to the development of molecular genetic and cytogenetic methods, the origin and development of the disease is gradually being elucidated. In addition to the cytogenetic changes that are part of the prognostic system (IPSS-R), the somatic mutations found in different genes come to the forefront of interest. However, they are not routinely used in clinical practice. One of the objectives of this study was monitoring of mutations in TP53 gene in lower-risk MDS patients who generally have a good prognosis and for whom these findings have a particularly relevant prognostic significance. We investigated a total of 154 patients with lower-risk MDS, and 13% of them had a mutation. After dividing patients according to the presence of del(5q), we observed significant differences in the incidence of the mutations. The mutations were detected in 23.6% of patients with...

The selection on genetic values predicted from markers could substantially increase the rate of genetic gain in animals by increasing accuracy of prediction and reducing generation interval, especially for difficult to measure traits, such as feed efficiency. Feed efficiency is the most important trait in animal production due to its impacts on cost of production and environmental factors. Many metrics measure the feed efficiency, such as ratio of gain to feed (FER), the ratio of feed to gain (FCR) and residual feed intake (RFI). Nevertheless, in ovine, no study with the aim of understand the genetic variants or the accuracy of genomic estimated breeding value (GEBV) for feed efficiency traits was published yet. Moreover, before to apply the genomic information, it is necessary to understand and characterized the population structure, for instance, by linkage disequilibrium (LD). Both genome-wide association studies (GWAS) and genomic selection (GS) leverage LD between marker and causal mutation. Based on the above considerations, the aim of this study was to map LD in ovine, characterized by Brazilian Santa Inês sheep; to search genetic variants for feed efficiency traits (FER, FCR and RFI) through GWAS; and to verify the accuracy of GEBV for RFI. In total, 396 samples (animals) of Longissimus dorsi muscle were collect. A high-density panel of SNP (Illumina High-Density Ovine SNP BeadChip®) comprising 54,241 SNPs was used to obtain the genotyping data. The phenotype data was comprised of 387 animals. The average LD between adjacent markers for two LD metrics, r² and |D\'|, were 0.166 and 0.617, respectively. The degree of LD estimated was lower than reported in other species and it was characterized by short haplotype blocks. Consequently, for genomic analyses, high-density panels of marker are recommended. Many markers were associated to feed efficiency traits in GWAS, mainly to RFI trait. Few candidate genes were reported in this study, highlighting NRF-1 (nuclear respiratory factor 1), which controls mitochondrial biosynthesis, the most important process responsible by a great fraction of the produced energy. Finally, we verified the accuracy of GEBV for RFI using few Bayesian regression models, and we found low accuracy, ranging from 0.033 (BayesB with π=0.9912) to 0.036 (BayesA), which might be explained by the low relationship among animals and small training population. / A seleção com base nos valores genéticos genômicos preditos pode aumentar substancialmente a taxa de ganho genético em animais por meio do aumento da acurácia de predição e redução do intervalo de gerações, especialmente para características de difícil e/ou onerosa mensuração, como eficiência alimentar. A eficiência alimentar é uma das características mais importantes na produção animal devido principalmente aos seus impactos econômicos e ambientais. Muitas métricas representam a eficiência alimentar, por exemplo: a relação do ganho de peso e consumo alimentar (EA), a proporção do consumo alimentar e ganho de peso (CA) e o consumo alimentar residual (CAR). Em ovinos, nenhum estudo com o objetivo de buscar variantes genéticas ou verificar a acurácia do valor genético genômico estimado para eficiência alimentar foi publicado. Adicionalmente, antes de aplicar a informação genômica, é necessário compreender e caracterizar a estrutura da população, como por meio do desequilíbrio de ligação (LD). O estudo de associação genômica (GWAS) e seleção genômica (GS) consideram o LD entre marcador e a mutação causal. Com base nas considerações acima, o objetivo deste estudo foi mapear o LD em ovinos, caracterizado pela raça ovina Santa Inês; localizar variantes genéticas para as características de eficiência alimentar (EA, CA e CAR) utilizando a abordagem GWAS; e verificar a acurácia da estimação dos valores genéticos genômico para o CAR. No total, foram coletadas 396 amostras (animais) do músculo Longissimus dorsi, para posterior genotipagem utilizando o painel de alta densidade (Illumina High-Density Ovine SNP BeadChip®), compreendendo 54.241 SNPs. O banco fenotípico é composto por 387 animais. O LD médio entre marcadores adjacentes para duas métricas de LD, r² e |D\'|, foram 0,166 e 0,617, respectivamente. O grau de LD estimado foi menor que o relatado em outras espécies e foi caracterizado por blocos de haplótipos curtos. Consequentemente, para as análises genômicas são recomendados painéis de marcadores de alta densidade. No GWAS, foram encontrados muitos marcadores associados aos fenótipos, em especial, à característica CAR. Alguns genes candidatos foram relatados neste estudo, destacando-se o NRF-1 (fator respiratório nuclear 1), que controla a biossíntese mitocondrial, o processo mais importante responsável por grande parte da produção de energia. Finalmente, verificamos a acurácia do valor genético genômico estimado para o CAR usando modelos de regressão Bayesiana, e encontramos baixos valores para acurácia (0,033 a 0,036) o que pode ser explicado pelo baixo grau de relacionamento entre os indivíduos e tamanho reduzido da população de treinamento.

Dans cette thèse, nous avons étudié l'influence de plusieurs variants génétiques situés dans les régions chromosomiques 5q31-q33, 6p21, et 17p12, pour lesquelles une liaison génétique avec des phénotypes de paludisme a été montrée.Les gènes NCR3 et TNF, qui sont situés dans la région chromosomique 6p21, ont été associés au paludisme dans une population vivant au Burkina Faso. Nous avons répliqué ces études dans une population congolaise afin deconfirmer les associations des polymorphismes avec les accès palustres simples et la parasitémie symptomatique. Nos résultats montrent que le polymorphismeNCR3-412 est associé avec les accès palustres simples au Congo, et que les polymorphismes TNF-308, TNF-244, et TNF-238 sont associés avec les accès palustres simples ou la parasitémie symptomatique. En outre, nos analyses bioinformatiques suggèrent que les polymorphismes TNF-244 et TNF-238 agissent en synergie pour modifier le site de fixation pour au moins un facteur de transcription.Les deux gènes HS3ST3A1 et HS3ST3B1, qui sont situés dans la région chromosomique 17p12, sont impliqués dans la biosynthèse des heparanes sulfates. Dans cette étude, nous avons étudié l'association d’un polymorphisme situé dans le promoteur de HS3ST3A1 avec les accès palustres simples et la parasitémie symptomatique, et n’avons détecté aucune association. Nous avons étudié en outre le gène NDST1, situé dans la région chromosomique 5q31-q33, et qui code également pour une enzyme impliquée dans la voie héparane sulfate. Des résultats préliminaires encourageants soutiennent l'hypothèse que la variation génétique de NDST1 influence la parasitémie asymptomatique. / In this thesis, we investigated the influence of some genetic variants located within chromosomes 5q31-q33, 6p21, and 17p12, which have been shown to be linked to malaria phenotypes. The genes NCR3 and TNF, which are located in the chromosomal region 6p21, have been reported to be associated with malaria in Burkina Faso population. We have replicated those studies in Congolese population to evaluate the associations of the SNPs in those genes with mild malaria attack and Plasmodium parasitemia. The results showed that the variant NCR3-412 is associated with mild malaria in Congo, and TNF-308, TNF-244, and TNF-238 are associated with mild malaria attack, maximum parasitemia, or both. In addition, bioinformatic studies suggest that TNF-244 and TNF-238 synergise to alter the binding of transcription factors.The two genes HS3ST3A1 and HS3ST3B1, which are located in chromosomal regions 17p12, are involved in the heparan sulfate proteoglycan biosynthesis. In this study, we further investigated the association of the polymorphisms in these genes with mild malaria attack and maximum parasitemia. However no association was found. We further studied the NDST1 gene, which is located within chromosome 5q31-q33, and which encodes the bifunctional enzyme N-deacetylase/ N-sulfotransferase 1, and also participates in the heparan sulfate synthesis . Encouraging results support the hypothesis that NDST1 variation influence controlling parasitemia. Further association and functional studies are needed to validate the role of NDST1 in malaria infection. More generally, the enzymes involved in the heparan sulfate pathway might play a key role in controlling malaria infection.

Males and age group 1 to 5 years show a much higher risk for childhood acute lymphoblastic leukemia (ALL). We performed a case-only genome-wide association study (GWAS), using the Illumina Infinium HumanCoreExome Chip, to unmask gender- and age-specific risk variants in 240 non-Hispanic white children with ALL recruited at Texas Children’s Cancer Center, Houston, Texas. Besides statistically most significant results, we also considered results that yielded the highest effect sizes. Existing experimental data and bioinformatic predictions were used to complement results, and to examine the biological significance of statistical results. Our study identified novel risk variants for childhood ALL. The SNP, rs4813720 (RASSF2), showed the statistically most significant gender-specific associations (P < 2 x 10-6). Likewise, rs10505918 (SOX5) yielded the lowest P value (P < 1 x 10-5) for age-specific associations, and also showed the statistically most significant association with age-at-onset (P < 1 x 10-4). Two SNPs, rs12722042 and 12722039, from the HLA-DQA1 region yielded the highest effect sizes (odds ratio (OR) = 15.7; P = 0.002) for gender-specific results, and the SNP, rs17109582 (OR = 12.5; P = 0.006), showed the highest effect size for age-specific results. Sex chromosome variants did not appear to be involved in gender-specific associations. The HLA-DQA1 SNPs belong to DQA1*01:07and confirmed previously reported male-specific association with DQA1*01:07. Twenty one of the SNPs identified as risk markers for gender- or age-specific associations were located in the transcription factor binding sites and 56 SNPs were non-synonymous variants, likely to alter protein function. Although bioinformatic analysis did not implicate a particular mechanism for gender- and age-specific associations, RASSF2 has an estrogen receptor-alpha binding site in its promoter. The unknown mechanisms may be due to lack of interest in gender- and age-specificity in associations. These results provide a foundation for further studies to examine the gender- and age-differential in childhood ALL risk. Following replication and mechanistic studies, risk factors for one gender or age group may have a potential to be used as biomarkers for targeted intervention for prevention and maybe also for treatment.

<div>This dissertation consists of two parts. The first part is a collaborative project with Dr. Szymanski's group in Agronomy at Purdue, to predict protein complex assemblies and interactions. Proteins in the leaf cytosol of Arabidopsis were fractionated using Size Exclusion Chromatography (SEC) and mixed-bed Ion Exchange Chromatography (IEX).</div><div>Protein mass spectrometry data were obtained for the two platforms of separation and two replicates of each. We combine the four data sets and conduct a series of statistical learning, including 1) data filtering, 2) a two-round hierarchical clustering to integrate multiple data types, 3) validation of clustering based on known protein complexes,</div><div>4) mining dendrogram trees for prediction of protein complexes. Our method is developed for integrative analysis of different data types and it eliminates the difficulty of choosing an appropriate cluster number in clustering analysis. It provides a statistical learning tool to globally analyze the oligomerization state of a system of protein complexes.</div><div><br></div><div><br></div><div>The second part examines global hypothesis testing under sparse alternatives and arbitrarily strong dependence. Global tests are used to aggregate information and reduce the burden of multiple testing. A common situation in modern data analysis is that variables with nonzero effects are sparse. The minimum p-value and higher criticism tests are particularly effective and more powerful than the F test under sparse alternatives. This is the common setting in genome-wide association study (GWAS) data. However, arbitrarily strong dependence among variables poses a great challenge towards the p-value calculation of these optimal tests. We develop a latent variable adjusted method to correct minimum p-value test. After adjustment, test statistics become weakly dependent and the corresponding null distributions are valid. We show that if the latent variable is not related to the response variable, power can be improved. Simulation studies show that our method is more powerful than other methods in highly sparse signal and correlated marginal tests setting. We also show its application in a real dataset.</div>

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13398号 / 論医博第2222号 / 新制||医||1051(附属図書館) / (主査)教授 妹尾 浩, 教授 中山 健夫, 教授 西浦 博 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>Within the last few decades, swine breeding programs have been refined to include pork quality and novel carcass traits alongside growth, feed efficiency, and carcass leanness in the selection programs for terminal sire lines with a goal to produce high quality and efficient pork product for consumers. In order to accurately select for multiple traits at once, it becomes imperative to explore their genetic and biological architecture. The genetic architecture of traits can be explored through the estimation of genetic parameters, genome-wide association studies (GWAS), gene networks and metabolic pathways. An alternative approach to explore the genetic and biological connection between traits is based on principal component analysis (PCA), which generates novel “pseudo-phenotypes” and biological types (biotypes). In this context, the main objective of this thesis was to understand the genetic and biological relationship between three growth, eight conventional carcass, 10 pork quality, and 18 novel carcass traits included in two studies. The phenotypic data set included 2,583 records from female Duroc pigs from a terminal sire line. The pedigree file contained 193,764 animals and the genotype file included 21,344 animals with 35,651 single nucleotide polymorphisms (SNPs). The results of the first study indicate that genetic progress can be achieved for all 39 traits. In general, the heritability estimates were moderate, while most genetic correlations were generally moderate to high and favorable. Some antagonisms were observed but those genetic correlations were low to moderate in nature. Thus, these relationships can be considered when developing selection indexes. The second study showed that there are strong links between traits through their principal components (PCs). The main PCs identified are linked to biotypes related to growth, muscle and fat deposition, pork color, and body composition. The PCs were also used as pseudo-phenotypes in the GWAS analysis, which identified important candidate genes and metabolic pathways linked to each biotype. All of this evidence links valuable variables such as belly, color, marbling, and leanness traits. Our findings greatly contribute to the optimization of genetic and genomic selection for the inclusion of valuable and novel traits to improve productive efficiency, novel carcass, and meat quality traits in terminal sire lines.<br></p><p></p>

Nitrogen (N) is a central nutrient in cropping systems. However, a considerable N fraction is lost through runoffs and leaching with detrimental consequences for environment and controversial effects on human health. Increasing the plant N uptake by optimizing the degree of root branching for exploring a larger soil volume in search of the mobile nitrate resource may contribute to limit soil leaching and subsequently to rely more efficiently on the soil mineralization and fertilizer inputs. Rapeseed (Brassica napus L.) is a major oil crop that highly depends on N fertilization. This doctoral thesis aims at exploring the diversity of root morphology in recently selected cultivars and in a large set of rapeseed inbred lines, and at understanding the genetic control on root morphology and how it is impacted by N nutrition.Firstly, a panel of twenty-eight European recently selected cultivars of winter oilseed rape were tested in laboratory and field conditions. Upon hydroponic culture, these hybrids showed a great diversity for biomass production and root morphological traits. Differences in root and shoot dry biomasses and lateral root length were mainly explained by the genotype, while differences in primary root length by the nutrition. The cultivars were tested in a pluriannual field trial. The observed variation for yield and seed quality traits attributed to the genotype was more important than the year or the genotype x year interaction effects. The total root length measured in laboratory could predict the proportion of nitrogen taken-up from the field and reallocated to the seeds. The genetic interrelationship between cultivars, established with polymorphic markers, indicated a very narrow genetic base. Positive correlations were found between the genetic distance measures, root morphological trait distances during nitrogen depletion conditions, and agronomic performance. Secondly, three cultivars previously selected from a root morphology screen at a young developmental stage were field tested with two nitrogen applications. The purpose was to examine the relationship between root morphology and Nitrogen Uptake Efficiency (NUpE) and to test the predictiveness of canopy optical indices for seed quality and yield. A tube-rhizotron system was used to incorporate below-ground root growth information. One-meter length clear tubes were installed in soil at an angle of 45°. The root development was followed with a camera at key growth stages in autumn (leaf development) and spring (stem elongation and flowering). Autumn was a critical time window to observe the root development and exploration in deeper horizons (36-48 cm) was faster without any fertilization treatment. Analysis of the rhizotron images was challenging and it was not possible to clearly discriminate between cultivars. Canopy reflectance and leaf optical indices were measured with proximal sensors. The Normalized Difference Vegetation Index (NDVI) was a positive indicator of biomass and seed yield while the Nitrogen Balance Index (NBI) was a positive indicator of above-ground biomass N concentration at flowering and seed N concentration at harvest.Thirdly, the natural variability offered by a diversity set of 392 inbred lines was screened to apprehend the genetic control of root morphology in rapeseed and how it is impacted by nitrogen nutrition. Seedlings grew hydroponically with low (0.2 mM) or elevated (5 mM) nitrate supplies. Low nitrate supply triggered the primary root and lateral root growth, while elevated supply promoted shoot biomass production. A considerable variation degree in the root morphological traits was observed across the diversity set, and there was no trade-off between abundant lateral root branching and shoot biomass production. Root traits were mainly dependent on the genotype and highly heritable. A genome wide association study identified some genomic regions associated with biomass production and root morphological traits. A total of fifty-nine QTLs were identified and thirty of them were integrated into seven clusters on chromosomes A01 and C07. Some candidate genes were identified with Arabidopsis orthologs related to root growth and development, nitrogen nutrition or hormone regulation.This study provides promising routes for redesigning the root system architecture by uncovering nitrogen-interactive genomic regions shaping root morphology. A perspective is to develop genetic markers associated with root morphological traits that could be used for assisted breeding. / Doctorat en Sciences agronomiques et ingénierie biologique / info:eu-repo/semantics/nonPublished

Major Depressive Disorder (MDD) is a complex and chronic disease that ranks fourth as cause of disability worldwide. Thirteen to 14 million adults in the U.S. are believed to have MDD and an estimated 75% attempt suicide making MDD a major public health problem. Recently several genome-wide association (GWA) studies of MDD have been reported; however, few GWA studies focus on the analysis for MDD related phenotypes such as neuroticism and age at onset of MDD. The purpose of this study is to determine risk factors for MDD, identify genome-wide genetic variants affecting neuroticism and age at onset as quantitative traits, and detect gender differences influencing neuroticism. Bivariate and multiple logistic regression analyses were performed on 1,738 MDD cases and 1,618 non-MDD controls to determine phenotypic risk factors for MDD. Multiple linear regression analyses in PLINK software were used for GWA analyses for neuroticism and age at onset of MDD with 437,547 Single Nucleotide Polymorphisms (SNPs). Gender (OR: 1.43; 95% CI: 1.24 - 1.64) and a family history (OR: 2.88; 95% CI: 2.48 - 3.35) were significantly associated with an increased risk of MDD, which supports the findings of prior studies. Through GWA analysis 34 SNPs were identified to be associated with neuroticism (p < 10-4). The best SNP was rs4806846 within the TMPRSS9 gene (p = 7.79 x10-6). Furthermore, 46 SNPs were found showing significant gene x gender interactions for neuroticism with p<10-4. The best SNP showing gene x gender interaction was rs2430132 (p = 5.37x10-6) in HMCN1 gene. In addition, GWA analysis showed that several SNPs within 4 genes (GPR143, ASS1P4, MXRA5 and MAGEC1/2) were significantly associated with age at onset of MDD (p < 5x10-7). This study confirmed previous findings that MDD is associated with an increased prevalence in women (about 43% more compared to men) and is highly heritable among first degree relatives. Several novel genetic loci were identified to be associated with neuroticism and age at onset. Gender differences were found in genetic influence of neuroticism. These findings offer the potential for new insights into the pathogenesis of MDD.

Assortative Mating, the tendency for mate selection to occur on the basis of similar traits, plays an essential role in understanding the genetic variation on academic achievements and intelligence (IQ). It is an important mechanism explaining spousal concordance. We used principal component analysis (PCA) for spousal correlation. There is a significant positive correlation between spouses by the new variable PC1 (correlation coefficient=0.515, p<0.0001). We further research the genetic factor that affects IQ by using the same data. We performed a low density genome-wide association (GWA) analysis with a family-based association test to identify genetic variants that associated with intelligence as measured by WAIS full-score IQ (FSIQ). NTM at 11q25 (rs411280, p=0.000764) and NR3C2 at 4q31.23 (rs3846329, p=0.000675) were 2 novel genes that haven't been associated with IQ from other studies. This study may serve as a resource for replication in other populations and a foundation for future investigations.