Les cytokines sont d’importants médiateurs dans la physiopathologie des lymphomes hodgkiniens (LH). A partir d’une cohorte de 464 patients, nous avons évalué l’impact pronostique de onze SNPs parmi les gènes de cytokines : IL10 (rs1800890, rs1800896, rs1800871, rs1800872), TNFA (rs1800629) ; IL6 (rs1800795) ; IL1B (rs16944) ; ILRN (rs419598) ; INFG (rs2430561) ; IL12 (rs3212227) ; CCL17 (rs223828). Le génotypage du SNP de l’IL12 montre une distribution différente de celle attendue dans la population générale selon le test de Hardy-Weinberg. Ce résultat suggère que les variations génétiques de l’IL12 pourraient être impliquées dans la susceptibilité au LH. Les patients porteurs du génotype IL10-1082AA présentent un taux de rémission complète au traitement initial supérieur aux patients présentant un autre génotype (95% vs. 88% P = .02). Pour les patients de stade avancé III-IV, le taux de survie globale à 6 ans est statistiquement différent entre les génotypes IL10-592AA/CC/AC et IL10-819TT/CC/CT (100%, 94%, 78%, P = .03). Ce résultat est retrouvé pour les patients porteurs de LH n’exprimant pas l’EBV. Pour les LH EBV négatif, le taux de survie sans progression à 6 ans est différent en fonction du génotype du TNFA-308AA/GG/AG (100%, 84%, 68%, P = .03). Il n’a été pas retrouvé de corrélation entre les génotypes et les dosages plasmatiques de l’IL-10, TNFA, IL-1RA, IL-6. Cette étude montre que le ‘‘fond génétique immun’’ est important à prendre en considération pour définir le pronostic des patients. Le rôle des SNPs de l’IL10 et du TNFA dans les LH EBV négatif devra être confirmé ainsi que l’influence des variations génétiques de l’IL12 dans la susceptibilité au LH. / Cytokines are important immune mediators implicated in Hodgkin lymphoma (HL) pathogenesis but little is known on the role of immune gene variations. We assessed prospectively the prognostic role of cytokine gene single nucleotide polymorphisms (SNPs) in HL patients (pts) : IL10 (rs1800890, 448 pts; rs1800896, 459 pts ; rs1800871, 446 pts ; rs1800872, 447 pts), TNFA (rs1800629, 464 pts) ; IL6 (rs1800795, 201 pts) ; IL1B (rs16944, 198 pts) ; ILRN (rs419598, 199 pts) ; INFG (rs2430561, 200 pts) ; IL12 (rs3212227, 259 pts) ; CCL17 (rs223828, 198 pts). IL12 genotype distribution appears significantly different from what observed in general population according to Hardy-Weinberg test which was already observed in another published study. IL10-1082AA genotype was associated with better complete response than other IL10 genotypes (95% vs. 88% P = .02). For patients with stage III-IV HL, the 6-year overall survival was statistically different between IL10-592AA/CC/AC and IL10-819TT/CC/CT genotypes (100%, 94%, 78%, P = .03). This prognostic effect was observed in EBV-negative but not in EBV-positive HL. In EBV-negative HL, TNFA-308AA/GG/AG genotypes had a different 6-year progression-free survival (100%, 84%, 68%, P = .03). No correlation was observed between genotypes and IL-10, TNFA, IL-1RA, IL-6 cytokine levels. This exploratory study suggests an effect of IL10 and TNFA SNPs in predicting HL outcome but other studies are needed to decipher the role of the host immunogenetic background, in particular the relation with EBV. Regarding the IL12 genotyping results, whether IL12 polymorphism is implicated in HL susceptibility needs also to be clarify.

A expansão dos locais e da época de cultivo do milho faz com que uma fração significativa da produção do cereal ocorra em condições de estresses abióticos. Grande parte desse cenário edafoclimático remete ao cultivo do milho safrinha, semeado entre janeiro e março e atualmente responsável por 65% da produção total. Dentre os diversos tipos de estresses abióticos, a deficiência de nitrogênio é comum e crítica nos solos brasileiros. Evidencia-se, portanto, a necessidade do desenvolvimento de genótipos mais eficientes no uso de nitrogênio, resultando em benefícios econômicos e ambientais. Caracteres morfofisiológicos podem auxiliar no processo seletivo de genótipos superiores para essas condições, como a mensuração do sistema radicular e a análise da taxa fotossintética. Nesse contexto, o objetivo do trabalho foi identificar regiões do genoma do milho tropical associadas ao comprimento de raiz, à fluorescência de clorofila e ao índice de resposta da planta ao estresse por nitrogênio. Para isto, foram avaliadas 64 linhagens endogâmicas de milho tropical em baixa e alta disponibilidade nitrogênio no solo e em dois locais de cultivo na Região de Piracicaba-SP, nas safras 2014/15 e 2015/16. Foram considerados o comprimento de raiz, a eficiência fotossintética do fotossistema II e o Índice de Tolerância à Baixa disponibilidade de nitrogênio (ITBN). As linhagens foram genotipadas com a plataforma Affymetrix® Axiom® Maize Genotyping Array de 616.201 marcadores SNP. A qualidade da informação genômica foi controlada pelos procedimentos Minor Allele Frequency e Call Rate e pela eliminação de heterozigotos. Os valores genotípicos foram preditos por meio de equações de modelos mistos do tipo REML/BLUP. Os dados de marcadores moleculares e fenotípicos foram analisados por Associação Genômica Ampla (GWAS). Verificou-se maior comprimento radicular em condições de baixa disponibilidade de nitrogênio. No total, sete marcadores significativos foram identificados, sendo quatro referentes ao ITBN, dois referentes ao comprimento de raiz em disponibilidade ideal e um referente ao comprimento de raiz em disponibilidade baixa do nutriente. Entre os principais processos biológicos identificados através da anotação funcional, estão o controle e regulação da transcrição, detectado para todos os caracteres avaliados, e a síntese de Guanosina Monofosfato Sintetase (GMP), enzima diretamente envolvida na disponibilização e reciclagem de nitrogênio. Também foi observada coincidência de região cromossômica entre marcadores significativos identificados e QTL potencialmente relacionados com a eficiência no uso de nitrogênio já reportados na literatura. Conclui-se que a técnica GWAS apresenta eficiência na detecção de marcadores associados aos caracteres de interesse, neste caso evidenciando processos e funções celulares relacionados aos diferentes processos da síntese e reciclagem de nitrogênio. / The expansion of locals and season period of maize crop makes a significant portion of the cereal production to occur under abiotic stress conditions. Much of this environmental scenario refers to the second growing season maize, sowed between January and March and responsible for 65% of total production currently. Among the different types of abiotic stresses, nitrogen deficiency is common and critical in Brazilian soils. Therefore, it becomes necessary to develop genotypes more efficient in nitrogen use, resulting in economic and environmental benefits. Morphophysiological characters may assist in the selective process of superior genotypes for these conditions, such as root system measurement and photosynthetic ratio analysis. In this context, this project aimed to identify tropical maize genomic regions associated with root morphological character, physiological parameter of photosystem II, and with the plant response index to nitrogen stress. To this end, 64 tropical maize inbreeding lines contrasting for nitrogen use efficiency were evaluated in low and ideal soil nitrogen availability in two cultivation sites in the region of Piracicaba-SP, in seasons 2014/15 and 2015/16. The characters root total length, chlorophyll fluorescence, and Low Nitrogen Tolerance index (LNTI) were considered. The lines were genotyped SNP using the Affymetrix® Axiom® Maize Genotyping Array with 616,201 SNP. The quality of the genomic information was controlled by Minor Allele Frequency and Call Rate procedures and by the elimination of heterozygous loci. The genotypic values were predicted using REML/BLUP mixed model equations. Genome-Wide Association Studies (GWAS) was performed to analyze molecular and phenotypic data. Greater root length under low availability nitrogen conditions was verified. In total, seven significant markers were identified, four referring to LNTI, two referring to root length under ideal nitrogen availability and one referring to root length under low nitrogen availability. Among the main biological processes identified trough functional annotation are the transcription control and regulation, detected to all evaluated characters, and the synthesis of Guanosine Monophosphate Synthetase (GMP), enzyme directly involved in the provision and recycling of nitrogen. It was also observed coincidence of chromosomal region between significant markers identified and QTLs potentially related in nitrogen use efficiency previously reported. As conclusion, GWAS technique shows efficiency in the detection of markers associated to the characters in focus, in this evidencing cellular processes and functions associated to the different process of nitrogen synthesis and recycling.

O objetivo deste estudo foi identificar SNPs na região promotora e no intron I do gene GH (região alvo) e verificar sua possível associação com o crescimento de O. niloticus, o que foi executado em duas etapas: (1) prospecção de SNPs; (2) associação de SNPs com crescimento das variedades Red-Stirling e Chitralada. As análises de associação foram realizadas por meio de metodologia estatística baseada em análise univariada de modelo linear misto considerando-se efeitos fixos e aleatórios. Nove SNPs foram identificados no promotor (GHP1 a GHP9) e um na região 5 UTR (GHP10), os quais formaram 10 blocos genotípicos (A a J). Na população de associação seis novos blocos foram identificados (K a P). Os blocos B, P, K, L e M foram associados aos melhores pesos e os SNPs GHP6 a GHP10 demonstraram associação significativa (P < 0,05) como o crescimento. Portanto, foi possível estimar um conjunto de genótipos com maior efeito genético aditivo sobre o crescimento, o qual poderia ser utilizado em futuros programas de melhoramento genético assistidos por marcadores moleculares. / The present study aimed to identify SNPs in the proximal promoter region and in the first intron of GH gene and to evaluate if there is association of SNPs variation with the O. niloticus growth rate. Firstly, SNP searching in the two targeted regions was carried out in four strains. Then, two strains, Red-Stirling and Chitralada were used in grow-out testing in cages. Association between SNPs and growth rate were statistically estimated by univariate linear mixed model taking into account fixed and random effects. Nine SNPs were found in the proximal promoter region and one in the 5 UTR region, which formed 10 genotype blocks (A to J). Five of these genotype blocks (F to J) were not found in the grow-out individuals. However, six new genotype blocks (K to P) were identified. Genotype blocks B, P, K, L and M were statistically associated to the best weights, and the SNPs GHP6 to GHP10 individually showed significant association (P < 0,05) with growth. These findings found herein may potentially be used as Marked-Assisted Selection in tilapia breeding programs.

O objetivo deste estudo foi identificar SNPs na região promotora e no intron I do gene GH (região alvo) e verificar sua possível associação com o crescimento de O. niloticus, o que foi executado em duas etapas: (1) prospecção de SNPs; (2) associação de SNPs com crescimento das variedades Red-Stirling e Chitralada. As análises de associação foram realizadas por meio de metodologia estatística baseada em análise univariada de modelo linear misto considerando-se efeitos fixos e aleatórios. Nove SNPs foram identificados no promotor (GHP1 a GHP9) e um na região 5 UTR (GHP10), os quais formaram 10 blocos genotípicos (A a J). Na população de associação seis novos blocos foram identificados (K a P). Os blocos B, P, K, L e M foram associados aos melhores pesos e os SNPs GHP6 a GHP10 demonstraram associação significativa (P < 0,05) como o crescimento. Portanto, foi possível estimar um conjunto de genótipos com maior efeito genético aditivo sobre o crescimento, o qual poderia ser utilizado em futuros programas de melhoramento genético assistidos por marcadores moleculares. / The present study aimed to identify SNPs in the proximal promoter region and in the first intron of GH gene and to evaluate if there is association of SNPs variation with the O. niloticus growth rate. Firstly, SNP searching in the two targeted regions was carried out in four strains. Then, two strains, Red-Stirling and Chitralada were used in grow-out testing in cages. Association between SNPs and growth rate were statistically estimated by univariate linear mixed model taking into account fixed and random effects. Nine SNPs were found in the proximal promoter region and one in the 5 UTR region, which formed 10 genotype blocks (A to J). Five of these genotype blocks (F to J) were not found in the grow-out individuals. However, six new genotype blocks (K to P) were identified. Genotype blocks B, P, K, L and M were statistically associated to the best weights, and the SNPs GHP6 to GHP10 individually showed significant association (P < 0,05) with growth. These findings found herein may potentially be used as Marked-Assisted Selection in tilapia breeding programs.

Univerzita Karlova v Praze Přírodovědecká fakulta Studijní program: Doktorský studijní program v biomedicíně Studijní obor: Imunologie Mgr. Libor Kolesár Klinický význam polymorfismu cytokinových genů Clinical significance of cytokine gene polymorphism Disertační práce Vedoucí závěrečné práce/Školitel: Prof. MUDr. Ilja Stříž, CSc Praha 2012 Abstract The human genome is full of different sequence variants. They are different mainly in size but also in their influence on phenotype. The smallest unit of genetic polymorphism is single nucleotide polymorphism (SNP). SNPs represent a single nucleotide change between two alleles and might affect the gene expression. We have studied SNPs in three distinct fields as: (1) marker of risky patients after the organ transplantation, (2) diagnostic marker of patients with interstitial lung diseases (ILD) or (3) with uterine fibroid (UF). We have come to the following results. Ethnicity or even nationality plays a role in the distribution of genetic polymorphism. This must be absolutely taken into account when one would like to transfer findings of a clinical study from a certain nation or ethnic and applied them to his studied group for the comparative purposes. Our first clinical gene-association study has found that even gene polymorphism of the IL-18 gene may...

The objectives of this study were to identify signatures of selection in Bos taurus beef and dairy cattle populations and to annotate regions of selection with gene, function and QTL information. Differences in minor allele frequencies, population-average FST, population-specific FST, and integrated extended haplotype homozygosity scores were applied to a subset of the bovine HapMap data to characterize signatures of selection in 7 Bos taurus beef and 5 Bos taurus dairy cattle populations. Numerous single nucleotide polymorphisms (SNP) exhibited evidence of selection across the genome and regions of BTA2 and BTA14 that are considered to be under positive selection in beef and dairy cattle, respectively, were highlighted. The current density of SNP limited our ability to annotate regions putatively under selection because most SNP in the assay were intergenic. This is likely because of the betweenbreed SNP discovery method that was used, which typically identifies SNP with higher allele frequencies.

There is a strong need for powerful unified statistical methods for discovering underlying genetic architecture of complex traits with the assistance of omics information. In this paper, two methods aiming to detect novel association between the human genome and complex traits using intermediate omics data are developed based on statistical mediation modeling. We demonstrate theoretically that given proper mediators, the proposed statistical mediation models have better power than genome-wide association studies (GWAS) to detect associations missed in standard GWAS that ignore the mediators. For each ofthe modeling methods in this paper, an empirical example is given, where the association between a SNP and BMI missed by standard GWAS can be discovered by mediation analysis.

Regensburg, Univ., Diss., 2009.

Working with genomic information in cattle breeding has become a standard procedure. This study is focused on completion of missing genetic markers - SNPs (single nucleotide polymorphisms) - on genetic chips. More specifically completion of missing values in datasets which contain pieces of information about SNP occurence in cattle genome. These polymorfisms are used for evaluation of genomic relationship, prediction of genomic breeding values and for the valuation of tested animals. The most common chips used for genotyping are Illumina and Affymetrix. Each company develops its own techniques of genotype obtaining. Affymetrix has unified coding type of SNPs among chips of different generations and thus even older data can be used. Illumina uses many coding types between different generations of chips. Thus, direct comparison of SNPs is not possible. Illumina has chips of different density and financial costingness. Illumina chips have become a standard all over the world and it is used by all breeding companies. The most used software programs for imputations are Beagle, AlphaImpute, Impute 2, FindHap, DAGPHASE, FImputePedImpute and MaCH. Each software requires a relationship between genotyped individuals. In common breeding business the genotyping is not in train of generations. That is why our own methodological process was used. The aim of this study is to map the current research about the completion of missing genetic markers on genetic chips and to verify the calculation process. In total, it was created 8 models with different amount of tested SNPs. From 10 to 100 neighbouring loci was tested. The testing was processed at chosen loci in two datasets. Dataset A contained 260 bull genotypes of different breeds from the Czech Republic. Dataset B contained 3982 genotypes of pure Holstein bulls from nine countries. In the first case a very good results were obtained. The prediction of missing values was almost accurate with model reliability 100%. The only exception was for almost entirely homozygous loci where the reliability reached only 55%. When the second dataset was tested, the most extensive model reached the reliability of 80 90% even in case of homozygous loci. The prediction error value was higher than in the first case. It was proven that missing values prediction is possible to calculate using the neighbouring SNPs. The outputs of this study are to be the base for further study of genomic data.

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No. of bitstreams: 1 barros_cc_dr_jabo.pdf: 1109917 bytes, checksum: e1e4366545eb2571fb7432f8e1635b49 (MD5) Previous issue date: 2017-07-21 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Objetivou-se com o presente trabalho comparar diferentes métodos Bayesianos de predição genômica para as características de produção de leite (PL) e as porcentagens de gordura (%G) e proteína (%P) no leite de búfalas e, realizar um estudo de associação genômica ampla, a fim de identificar regiões cromossômicas e genes possivelmente relacionados às mesmas, utilizando informações de indivíduos genotipados e não genotipados. O número de animais com fenótipo foi 3.355, o arquivo de pedigree continha 15.495 animais, dos quais 322 foram genotipados com o 90 K Axiom® Buffalo Genotyping array. Os seguintes critérios de controle de qualidade dos SNPs foram utilizados: MAF < 0,05; Call Rate < 0,95 e Equilíbrio de Hardy-Weinberg p-value < 10-6. Em relação à amostra foi considerado call rate <0,90. Para as predições genômicas, os seguintes modelos Bayesianos foram utilizados: Bayes A (BA), Bayes B (BB), Bayes C (BC) e Bayes LASSO (BL). O fenótipo corrigido para os efeitos fixos (Y*) foi utilizado como variável resposta nas análises genômicas. A habilidade de predição dos diferentes modelos foi avaliada usando o método leave-one-out de validação cruzada. As acurácias de predição foram calculadas através da correlação de Pearson entre o valor genético genômico estimado (GEBV) e a variável resposta (Y*) para cada modelo e característica avaliados. Em relação ao estudo de associação genômica ampla, um processo iterativo foi realizado para calcular os pesos dos marcadores em função do quadrado dos efeitos dos SNPs e das frequências alélicas (ssGWAS). Em geral, todos os modelos Bayesianos demonstraram semelhantes acurácias de predição, variando de 0,41 a 0,42, 0,38 a 0,39 e 0,39 a 0,40 para a PL, %G e %P, respectivamente. Portanto, os métodos BA, BB, BC e BL podem ser utilizados nas predições dos efeitos dos SNPs, obtendo-se, praticamente, as mesmas acurácias de predição. Os dez SNPs de maiores efeitos para a PL, %G e %P explicaram 7,48, 9,94 e 6,56% da proporção da variância genética, respectivamente. Os resultados do ssGWAS revelaram regiões cromossômicas e genes que podem estar relacionados com as características analisadas. Tais regiões e genes identificados poderão contribuir para o melhor entendimento sobre a influência dos mesmos nas características produção de leite e as porcentagens de gordura e proteína no leite de búfalas. / The aim of this study was to compare different Bayesian methods of genomic prediction for milk yield (MY), fat (%F) and protein (%P) percentages in dairy buffaloes in Brazil, and to perform a genome-wide association study for the purpose of identify chromosomal regions and genes possibly related to the these traits, using information from genotyped and non-genotyped individuals. The number of animals with phenotype was 3,355, the pedigree file contained 15,495 animals, of which 322 were genotyped. The animals were genotyped using a 90K SNP panel (Axiom® Buffalo Genotyping Array). The following criteria for quality control of SNPs were used: MAF < 0.05, Call Rate < 0.95 and Hardy-Weinberg Equilibrium p-value < 10-6 . In relation to the sample, a Call Rate <0.90 was used. Four methods for genomic prediction were used: Bayes A (BA), Bayes B (BB), Bayes C (BC) and Bayes LASSO (BL). Phenotypes for the fixed effects (Y*) were used as response variables. The predictive ability of the different models was evaluated using a leave-one-out cross-validation approach. The prediction accuracy was calculated by Pearson's correlation between estimated genomic genetic value (GEBV) and response variable (Y*) for each model. In relation to genome-wide association studies, an iterative process was performed to derive SNP weights as function of squares of SNP effects and allele frequencies (ssGWAS). In general, all Bayesian models showed similar prediction accuracy, ranging from 0.41 to 0.42, 0.38 to 0.39 and 0,39 to 0,40 for MY, %F and %P, respectively. Therefore, the methods BA, BB, BC and BL can be used in the predictions of the effects of SNPs, obtaining, practically, the same prediction accuracy. The proportions of variance explained by the top 10 SNPs for MY, %F and %P were: 7.48, 9.94 and 6.56%, respectively. The results of ssGWAS revealed chromosomal regions and genes that may be related with the analyzed traits. These regions and genes may contribute to a better understanding of their influence on milk yield and fat and protein percentages in buffalo milk. / FAPESP: 2013/24427-3 / FAPESP: 2015/18614-0