Submitted by Angela Maria de Oliveira (amolivei@uepg.br) on 2018-12-04T18:41:29Z No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação_final_Adenilson.pdf: 1632453 bytes, checksum: ca3bab925a332585e719109a07462e72 (MD5) / Made available in DSpace on 2018-12-04T18:41:29Z (GMT). No. of bitstreams: 2 license_rdf: 811 bytes, checksum: e39d27027a6cc9cb039ad269a5db8e34 (MD5) Dissertação_final_Adenilson.pdf: 1632453 bytes, checksum: ca3bab925a332585e719109a07462e72 (MD5) Previous issue date: 2018-09-27 / Os objetivos deste trabalho foram a obtenção de um mapa genético de alta densidade utilizando marcadores SNP (Single Nucleotide Polymorphism) obtidos através de genotipagem por sequenciamento (GBS) e identificar as regiões genômicas ligadas à tolerância à murcha bacteriana (Ralstonia solanacearum Smith) em uma população de duplo-haploides (DH) de tabaco. As linhagens endogâmicas NC95 (tolerante) e NC2326 (suscetível) foram cruzadas entre si gerando a população F1, anteras foram coletadas destas plantas para produção de haploides e posterior duplicação cromossômica através da cultura de anteras, gerando 180 famílias duplo-haploides que foram avaliadas em ambiente controlado quanto à tolerância à murcha bacteriana, após inoculação com R. solanacearum, através de uma escala de notas com amplitude de 0 a 4. As famílias DH foram genotipadas utilizando a metodologia de GBS e os dados resultantes desta genotipagem foram alinhados com o genoma de referência do tabaco para posterior obtenção dos marcadores SNP utilizados na construção do mapa de ligação. O mapa de ligação juntamente com os dados de fenotipagem foram utilizados para realizar o mapeamento de QTLs através do mapeamento por intervalo composto. Foram identificados 6.842 SNPs, utilizados para construção de um mapa de ligação com 70.583 cM, sendo este o maior mapa de ligação utilizando marcadores SNP disponível para tabaco e com o maior número de marcadores. Utilizando este mapa de ligação foram mapeados 13 QTLs para tolerância à murcha bacteriana em oito grupos de ligação, dos quais oito QTLs ainda não tinham sido identificados na literatura especializada. Os locos presentes nos grupos de ligação 3, 17 e 22 apresentaram os maiores efeitos na variação fenotípica. O elevado número de QTLs mapeados nesta população confirma o padrão de herança quantitativa da tolerância de tabaco à murcha bacteriana causada por R. solanacearum. / The objectives of this work were to obtain a high-density genetic map using SNP (Single Nucleotide Polymorphism) markers obtained through Genotyping-by-Sequencing (GBS) and to identify the genomic regions linked to bacterial wilt tolerance (Ralstonia solanacearum Smith) in a tobacco double-haploid (DH) population. The inbred lines NC95 (tolerant) and NC2326 (susceptible) were crossed generating the F1 population, anthers were collected from these plants for haploid production and subsequent chromosomic duplication using anthers culture, generating 180 double-haploid families that were evaluated in a controlled environment for tolerance to bacterial wilt after inoculation with R. solanacearum, using an assessment scale from 0 to 4. The DH families were genotyped using the GBS methodology and the resulting data from this genotyping were aligned with the reference genome and then to obtain the SNP markers used to construct the genetic linkage map. The linkage map jointly with the phenotyping data were used to QTL mapping through the composite interval mapping method. A total of 6,842 SNPs was identified and used to construct a linkage map with 70,583 cM, being the largest SNP-based genetic linkage map available for tobacco and presenting the highest number of markers. Using this linkage map, 13 QTLs were mapped for bacterial wilt tolerance in eight linkage groups, from those eight QTLs had not yet been identified in the specialized literature. The loci present in linkage groups 3, 17 and 22 had the highest effects on phenotypic variation. The high number of QTLs mapped in this population confirms the quantitative genetic control of tobacco tolerance to bacterial wilt caused by R. solanacearum.

L'hyperchylomicronémie est une maladie rare et complexe impliquant plusieurs gènes qui sont eux-mêmes fortement régulés par plusieurs mécanismes et dont les voies métaboliques sont étroitement dépendantes de facteurs environnementaux. La survenue de la pathologie due à la présence de variants ou d'une association de variants sur ces gènes n'est pas toujours clairement définie. Ce qui suggère l'intervention d'autres mécanismes mal élucidés dans le développement des hyperchylomicronémies et la régulation du métabolisme des triglycérides. Nous avons essayé d'appréhender certains mécanismes causals dans la survenue de l hyperchylomicronémie en lien avec la présence de variants sur les gènes régulateurs APOC3 et LMF1 du métabolisme des triglycérides. Le gène APOC3 présente le variant SstI (rs5128) en région 3' non codante associée significativement à l'hypertriglycéridémie dans notre cohorte, nous avons cherché à caractériser sa régulation post-transcriptionnelle éventuelle par des microARN hépatiques ou intestinaux. Nos résultats ne confirment pas l'hypothèse d'une régulation du variant SstI du gène APOC3 par un microARN hépatique ou intestinal ciblant directement l'extrémité 3'UTR du gène APOC3. Le gène LMF1, nouveau gène candidat pour étudier les mécanismes des hyperchylomicronémies, est encore peu investigué. Nous avons mis en place son diagnostic génétique au sein du laboratoire ainsi qu'une technique in vitro permettant d'évaluer l'impact de la présence de certains variants codants de LMF1 sur l'activité post héparinique de la lipoprotéine lipase (LPL) par mesure de la lipolyse des triglycérides des VLDL. Nous avons mis en évidence des activités LPL significativement diminuées suggérant une dysfonction de LMF1 en présence des variants p.Gly172Arg (rs201406396), p.Arg354Trp (rs143076454), p.Arg364Gln (rs35168378), et des deux variants non-sens déjà décrits p.Tyr439Ter (rs121909397) et p.Trp464Ter (rs587777626). Ces travaux permettent de confirmer l'effet fonctionnel des variants LMF1 sur la régulation de la sécrétion de la LPL. Nous avons également retrouvé dans notre cohorte de 385 patients 18 variants sur la région 3' non codante du gène LMF1. Pour les trois variants : c*231C>A (rs75476513), c*512G>A (rs117039680), et c*530G>A (rs139657279), les résultats in vitro suggèrent une régulation post transcriptionnelle par les microARN. Ce qui pourrait ainsi expliquer le mécanisme de l'association de ces variants non traduits à l'hypertriglycéridémie. Ainsi, des interrelations des multiples gènes impliqués dans le métabolisme des triglycérides et leurs régulations à plusieurs niveaux simultanés modulent le phénotype d'hyperchylomicronémie. Il est nécessaire d'étudier tous les mécanismes complexes impliqués dans la régulation de la triglycéridémie afin de mieux appréhender la physiopathologie et de développer de nouvelles cibles thérapeutiques / Hyperchylomicronemia is a rare and complex disease involving several genes which are themselves highly regulated by several mechanisms and whose metabolic pathways are closely dependent on environmental factors. The occurrence of this disease due to the presence of variants or a combination of variants on these genes is not always clearly defined. This suggests the intervention of other ill-defined mechanisms in the development of hyperchylomicronemia and the regulation of triglyceride metabolism. We have tried to understand certain causal mechanisms in the occurrence of hyperchylomicronemia in relation to the presence of variants on the APOC3 and LMF1 known regulatory genes of triglyceride metabolism. APOC3 gene carries the SstI variant (rs5128) in the 3' untranslated region significantly associated with hypertriglyceridemia in our cohort. We sought to characterize its possible post-transcriptional regulation by hepatic or intestinal microRNA. Our results obtained in vitro do not support the hypothesis of a regulation of the SstI variant of the APOC3 gene by a hepatic or intestinal microRNA directly targeting the 3'UTR of APOC3 gene. LMF1 gene, a new candidate gene for studying the mechanisms of hyperchylomicronaemias, is still under investigation. We have established its genetic diagnosis in the laboratory and set up an in vitro method to evaluate the impact of LMF1 coding variants by measuring the release of post-heparin lipoprotein lipase (LPL) activity. We found decreased LPL activities suggesting a LMF1 dysfunction in the presence of variants p.Gly172Arg (rs201406396), p.Arg354Trp (rs143076454), p.Arg364Gln (rs35168378), and the two nonsense variants already described p.Tyr439Ter (rs121909397) and p.Trp464Ter (rs587777626). This study confirms the functional effect of LMF1 variants on the regulation of LPL secretion. In addition, we found 18 variants on the 3' untranslated region of LMF1 gene. For three variants : c*231C>A (rs75476513), c*512G>A (rs117039680), and c*530G>A (rs139657279), in vitro results suggest a post-transcriptional regulation by microRNA. These findings are an involvement of these untranslated variants in the occurrence of hypertriglyceridemia.Thus, complex interrelations of multiple genes involved in triglyceride metabolism and their simultaneous multi-level regulation modulate the phenotype of hyperchylomicronemic patients. It is necessary to study all the complex mechanisms involved in the regulation of triglyceridemia in order to better understand pathophysiology of hyperchylomicronemia and to develop new therapeutic targets

Depuis que Parsons et col. ont découvert en 2008 que le gène de l’isocitrate déhydrogénase 1 (IDH1) est fréquemment muté dans les glioblastomes (12%), de nombreuses équipes ont étudié la prévalence et les caractéristiques des mutations des gènes IDH1 et 2 dans les gliomes.Les mutations du gène IDH1 sont observées dans environ 40% des gliomes. La mutation d’IDH1 la plus fréquentes dans les gliomes (>90% des cas) est la mutation R132H. La fréquence des mutations IDH1 et 2 est inversement corrélée au grade des gliomes (grade II ~80%, III ~50%, and IV ~10%). Les mutations IDH1/2 ont une valeur diagnostique ainsi que pronostique (associées à une meilleure survie). Pendant ce travail de thèse nous avons dans une première partie analysé la distribution de ces mutations IDH1/2 dans les différents gliomes, leur association avec d’autres altérations génétiques, ainsi que leur valeur diagnostique et pronostique dans une cohorte de 1332 patients atteints de gliomes. Nous confirmons sur cette très grande cohorte les données de la littérature et affinons la valeur pronostique des mutations IDH1/2. Dans une seconde partie, nous avons mis en évidence dans les gliomes un polymorphisme (SNP) du gène IDH1 (SNP rs 11554137; C (cytosine) substituted by T (thymin)) précédemment observé dans les leucémies myéloïdes aigues. Ce SNP, codon 105, est localisé dans le même exon que le codon 132 fréquemment muté, et nous avons montré qu’il est associé à une moins bonne survie des patients atteints de gliomes. Les mutations du codon 132 causent une baisse de l’activité enzymatique normale d’IDH1/2 qui est remplacé par le gain d’une nouvelle. Les protéines IDH1/2 mutés, au lieu de produire de l’alpha-cétoglutarate de façon NADP dépendante, réduisent de façon NADPH dépendante l’alpha-cétoglutarate en 2-hydroxyglutarate (2HG). Une forte concentration de 2HG et une baisse de la quantité de NADPH peuvent sensibiliser les tumeurs au stress oxidatif et donc potentialiser l’effet de la radiothérapie, ce qui pourrait expliquer la meilleure survie de ces patients. Nous avons donc dans une troisième partie étudié in vitro l’impact de la mutation IDH1R132H sur la survie après radiothérapie de cellules tumorales exprimant de façon stable ce gène muté. Les résultats obtenus montrent que dans certaines conditions ces cellules pourraient être plus radiosensibles que les mêmes cellules exprimant le gène IDH1 non-muté.Dans ce travail de thèse, nous avons donc étudié le gène IDH1 dans les gliomes de patients et tenté par une approche fonctionnelle in vitro d’évaluer l’impact de la mutation IDH1R132H sur la radiosensibilité des cellules tumorales. / Since Parsons et al. (2008) found the frequent mutations of IDH1 (12%) in GBMs, various reports have studied the prevalence and characteristic of IDH1 and IDH2 mutations.The mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in nearly 40% of gliomas. The frequency of IDH1 mutations are inversely connected with grade II (~80%), III (~50%), and IV (~ 10%) gliomas. Importantly, the status of IDH1 mutations is associated with a better outcome and demonstrated a diagnostic value. We analyzed also these mutations in distribution, association with tumor-derived other genetic alterations and the diagnostic and prognostic value in a cohort of 1332 glioma patients.A synonymous single nucleotide polymorphism [SNP rs 11554137; C (cytosine) substituted by T (thymin)] has been studied in gliomas patients. The SNP rs 11554137 (in codon 105) are located in the same exon with the IDH1 R132 mutations (in codon 132). And gliomas patients with SNP rs 11554137: C>T had a poorer outcome than patients without SNP rs 11554137. This was observed a similarly adverse effect in survival in patients with AML. Mutations in codon 132 can cause a decrease of IDH1/2 activity and also gain a new enzyme function for the NADPH dependent reduction of alpha-ketoglutarate to 2-hydroxyglutarate. High 2HG and low NADPH levels might sensitize tumors to oxidative stress, potentiating response to radiotherapy, and may account for the prolonged survival of patients harboring the mutations. So we studied further the alterations of function in IDH1R132H mutant cells in vitro. Based on the decrease of defence and the increase of impairing factors in tumor cells, we found that the tumors harbouring IDH1 mutations may have an elevated radiosensitivity. In the present study, we described the impact of IDH1 mutations in gliomas and search for new perspectives for the treatment strategy.

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

O presente estudo avaliou o perfil farmacogenômico de 338 pacientes, sob terapia antiagregante. Os pacientes foram submetidos a tratamento prévio com AAS (100mg/dia) e clopidogrel (75mg/dia) por no mínimo cinco dias antes da angioplastia coronária. Os indivíduos com resposta considerada indesejada <30% de inibição de PRU (do inglês, P2RY12 Reaction Unit) para clopidogrel e >550 ARU (do inglês, Aspirin Reaction Unit), foram considerados como não respondedores. As concentrações plasmáticas dos antiagregantes foram determinadas por cromatografia líquida acoplada à espectrometria de massa do tipo triploquadrupolo (LC-MS/MS). A taxa da inibição da agregação plaquetária foi medida utilizando-se o sistema VerifyNow®. A expressão gênica global das células totais do sangue periférico foi avaliada pela tecnologia de microarranjos de DNA Human Exon ST 1.0 Array. Características genotípicas dos pacientes também foram avaliadas pelo sistema Sequenom®. Assim, foi possível obter como resultados a identificação de 64% e 10% para pacientes não respondedores ao clopidogrel e AAS respectivamente, sendo que para o primeiro foi possível identificar a associação desta não resposta a variáveis clínicas como diabetes (p = 0,003), hipertensão (p = 0,011) e hábito de fumar (p = 0,041) e sexo (p = 0,022) e idade dos pacientes (p = 0,004) em relação à resposta ao AAS. O método de quantificação simultânea do clopidogrel, seu metabólito majoritário e do AS (metabólito do AAS), apresentou limites de quantificação entre de 2 a 500 ng/mL, 2 a 2000 ng/mL e de 20 a 2000 ng/mL, respectivamente. O estudo de associação encontrou uma relação significante da presença dos SNPs presentes nos genes CYP5A1 (rs2299890) e CYP2C19 (rs4244285 e rs3758580), com a variação na resposta ao clopidogrel, obtendo um valor de p corrigido pelo teste de permutação inferior a 0,001. Como também, uma fraca associação da variação na resposta do AAS com o SNP rs9605030 do gene COMT (p = 0,009). Os resultados do microarranjos relacionaram a resposta terapêutica ao clopidogrel com os genes CA2, MKRN1, ABCC3 e MBP seguido dos genes NFIA e IGF1R para a resposta ao AAS. Concluindo que o estudo farmacogenômico apresentou todo o seu potencial para relacionar variáveis como resposta, concentração farmacológica plasmática, SNPs e expressão global de RNAm, possibilitando assim compreender melhor a variação no tratamento antiagregante. / This study investigated the pharmacogenomics profile of 338 patients under antiplatelet therapy. Patients undergoing pretreatment with ASA (100 mg/day) and clopidogrel (75mg/day) for at least five days prior to coronary angioplasty. Individuals with response <30% of PRU (P2RY12 reaction unit) were considering non responder for clopidogrel and >550 of ARU (aspirin reaction unit), were considered as non responders for ASA. Plasma concentrations of the antiagregation drugs were determined by liquid chromatography followed mass spectrometry of triple quadrupole detection (LC-MS/MS). The rate of inhibition of platelet aggregation was measured using the VerifyNow® system. The global gene expression of total cells in blood was assessed by DNA microarray technology Human Exon 1.0 ST Array. Genotypic characteristics of the patients were also evaluated by the Sequenom® system. Thus it was possible to obtain results such as identification of 64% and 10% for patients non responders to clopidogrel and aspirin respectively, and for the first could identify the association of this response to variables such as diabetes (p = 0.003), hypertension (p = 0.011) and smoking (p = 0.041) for clopidogrel and sex and age in relation to response to ASA (p = 0.022 and p = 0.004, respectively). The method of simultaneous quantification of clopidogrel and its major metabolite of AS (metabolite of ASA), had quantification limits between 200 to 500 ng/mL 2000-2000 ng/mL and 20 to 2000 ng/mL, respectively. The association study found a significant grating presence of SNPs present in genes CYP5A1 (rs2299890) and CYP2C19 (rs4244285 and rs3758580), with the variation in the response to clopidogrel, obtaining a corrected p value by permutation test below 0.001. As well, a weak association of variation in the response of ASA with the SNP rs9605030 of the gene COMT (p = 0.009). The results of microarray related therapeutic response to clopidogrel with genes CA2, MKRN1, ABCC3 and MBP followed by NFIA and IGF1R genes for response to ASA. Concluding that the pharmacogenomics study showed its potential to relate variables such as response, plasma drug concentration, SNPs and global expression of mRNA, thus enabling better understand the variation in antiplatelet treatment.

Introdução: Fatores genéticos estão entre os determinantes de obesidade, podendo influenciar a resposta a intervenções em estilo de vida. O impacto de polimorfismos de nucleotídeo único (SNPs) na resposta de biomarcadores a intervenções não é claro. Objetivo: Este estudo examinou as associações de seis SNPs FTO T/A, PPAR Pro12Ala, Apo A1 -75G/A, TNF- -308G/A, IL-6 - 174G/C e AdipoQ 45T/G com mudanças induzidas por uma intervenção em amostra de brasileiros de risco cardiometabólico. Métodos: Em um programa de nove meses de orientações em hábitos alimentares e atividade física, 180 indivíduos com prediabetes ou síndrome metabólica foram genotipados e agrupados segundo a presença do alelo variante de cada SNP e comparados quanto a variáveis antropométricas, metabólicas e inflamatórias. Resultados: A intervenção resultou em redução do consumo calórico, aumento da atividade física, melhora na antropometria e outros biomarcadores. Estratificando pelos SNPs, os principais achados estão contidos em dois artigos. Artigo 1: Houve melhor resposta do perfil glicêmico após a intervenção nos portadores do alelo variante do SNP TNF -308 G/A. Observou-se melhora das variáveis lipídicas nos portadores do alelo variante do SNP IL-6 -174 G/C, enquanto que aqueles com o genótipo referência obtiveram melhora no metabolismo da glicose. Carreadores do SNP AdipoQ 45T/G não obtiveram melhora no perfil lipídico nem no glicêmico.Artigo 2: O alelo variante do FTO T/A associou-se a melhores perfis 9 inflamatório e glicêmico em resposta à intervenção. Portadores do alelo variante do SNP PPAR Pro12Ala obtiveram melhora na pressão arterial, enquanto que indivíduos com o genótipo referência melhoraram o metabolismo lipídico. Carreadores do alelo variante do SNP Apo A1 -75G/A apresentaram melhora no perfil lipídico que, após ajuste para medicação, não se manteve significante. Conclusões: SNPs relacionados à obesidade e comorbidades podem influenciar a resposta de marcadores metabólicos e inflamatórios a intervenções em hábitos de vida em brasileiros. O SNP TNF -308G/A parece favorecer um melhor perfil glicêmico. O SNP IL-6 -174G/C pode conferir efeito benéfico no perfil lipídico, mas não na glicemia. O SNP AdipoQ 45T/G compromete a resposta à intervenção em indivíduos de risco cardiometabólico no nosso meio. O SNP FTO T/A pode favorecer a resposta do metabolismo da glicose e a atenuação da inflamação. O SNP PPAR Pro12Ala pode ter impacto benéfico na pressão arterial, mas não no metabolismo lipídico. Em contraste com a literatura, o SNP Apo A1 -75G/A não parece influenciar resposta dos lípides à intervenção. Mais estudos envolvendo estes SNPs são necessários para possível direcionamento de intervenções a subgrupos específicos de indivíduos de risco. / Introduction: Genetic factors are one of the determinants of obesity and may influence the response to interventions. The impact of single nucleotide polymorphisms (SNPs) in weight loss and inflammatory response to interventions is not clear. Objective: This study examined associations of six polymorphisms FTO T/A, PPAR Pro12Ala, Apo A1 -75G/A, TNF- -308G/A, IL-6 -174G/C and AdipoQ 45T/G with changes induced by lifestyle intervention in Brazilians at cardiometabolic risk. Methods: In a 9-month intervention on diet and physical activity, 180 individuals with prediabetes or metabolic syndrome were genotyped and compared according the presence of variant allele of the SNPs and antrophometric, metabolic and inflammatory variables. Results: The intervention resulted in lower energy intake and greater total physical activity as well as improvement in anthropometry and several biomarkers. Stratified by SNPs, the main findings are covered in two articles. Article 1: Variant allele carriers of TNF -308 G/A SNP decreased plasma glucose after intervention. Lipid profile improved after intervention in variant allele carriers of IL-6 -174 G/C, while individuals with reference genotype had better plasma glucose response. Variant allele carriers of AdipoQ 45T/G did not improve lipid and glycemic profile. Article 2: Only variant allele carriers of FTO T/A decreased fasting plasma glucose and C-reactive protein concentration after intervention. Blood pressure reduced after intervention in variant allele carriers of the PPAR Pro12Ala, while the reference genotype increased Apo A1. Apparent favorable response of lipid profile to intervention in variant allele carriers of Apo A1 -75G/A was not maintained after adjustments for lipid-lowering medication. Conclusions: SNPs associated with obesity and comorbidities may influence the response of metabolic and inflammatory markers after lifestyle intervention. The TNF -308G/A may predispose a better response of glucose metabolism. The IL-6 -174 G/C SNP may confer a beneficial effect on lipid profile but not in glucose metabolism. Our findings reinforce unfavorable effects of the AdipoQ 45T/G SNP in lipid and glucose metabolism after lifestyle intervention in Brazilians at cardiometabolic risk. FTO T/A SNP induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPAR Pro12Ala seems to favor a better lipid profile, while the variant allele to decrease blood pressure. In contrast to literature, our data did not support benefits on lipid profile of the variant allele of Apo A1 -75G/A SNP. Further studies of these SNPs are needed to direct interventions to specific subgroups of at-risk individuals.

Amaciamento natural devido proteólise miofibrilar pelas enzimas calpaínas (cálcio-dependentes) e descoloração devido oxidação do pigmento mioglobina podem ocorrer em carne maturada. Em bovinos, o tipo biológico Bos indicus apresenta maior atividade de calpastatina (CAST, inibidora das calpaínas) no músculo e concentração de melanina (modulador de vitamina D3) na pele do que Bos taurus. Maior concentração de melanina na pele reduz fotossíntese de vitamina D3 e, subsequentemente, poderia reduzir as concentrações de seus metabólitos 25-hidróxivitamina D3 (25-D) e 1,25-di-hidróxi-vitamina D3 (1,25-D; modulador de cálcio) no plasma de Bos indicus. Nos casos de maiores concentrações de 1,25-D plasmático, uma melhor absorção de cálcio da dieta com aumento de suas concentrações no plasma e músculo poderia resultar em atividade melhorada das calpaínas. Além disso, maiores concentrações de 1,25-D plasmático poderiam colaborar para minimizar oxidação de carne devido sua propriedade antioxidante. Então, além da maior atividade de CAST no músculo, os Bos indicus poderiam ter mais duas desvantagens para produzir carne mais macia e menos oxidada: concentrações maiores de melanina na pele e menores de 1,25-D no plasma. Desta forma, o objetivo deste trabalho foi estudar as relações entre as concentrações de melanina total (MELT) e suas frações [faeumelanina (FAE) e eumelanina (EUM)] na pele, metabólitos da vitamina D3 (25-D e 1,25-D) no plasma, cálcio plasmático e muscular e maciez [Índice de Fragmentação Miofibrilar (MFI) e força de cisalhamento (FC)] e cor (valores de L*, a* e b*) em carne maturada (1, 7 e 14 dias) e suas associações com polimorfismos de um único nucleotídeo (SNPs) nos genes candidatos receptor da melanocortina-1 [MC1R; rs109688013 (C/T) e rs110710422 (G/-)], proteína ligante à vitamina D3 [DBP; rs136359868 (T/C) e rs135330728 (T/C)] e CAST [rs109384915 (T/C)]. Bovinos Nelore (n=86), abatidos com 516 ± 39 kg aos 24 ± 1 meses, foram usados para determinação dos genótipos e mensuração das características. Na pele, a fração EUM foi positivamente correlacionada com MELT, mais do que a fração FAE. As frações de melanina na pele foram correlacionadas negativamente. A fração FAE foi correlacionada negativamente com 1,25-D plasmático, mas não foi correlacionada com 25-D plasmático. Melanina e suas frações na pele e metabólitos da vitamina D3 no plasma não foram correlacionadas com cálcio plasmático e muscular. Todavia, cálcio no plasma e músculo foram correlacionados positivamente com MFI e valores de L* e b* e negativamente com FC e valores de a*. A EUM e MELT na pele foram correlacionadas negativamente com FC e valores de a* e b* e positivamente com valores de L*, enquanto que 25-D no plasma foi correlacionada positivamente com MFI e valores de a* e b* e negativamente com valores de L*. A FAE foi correlacionada positivamente com MFI e negativamente com os valores de L*, a* e b*. No gene MC1R, o alelo T do SNP rs109688013 apresentou-se fixado (100%) na população, enquanto que o alelo G e sua deleção (-) do SNP rs110710422 tiveram frequência de 97,7 e 2,3%, respectivamente. SNPs do gene MC1R resultaram nos genótipos do loco Extension (E/E = T/T + G/G e E/e = T/T + G/-), que foi associado com 1,25-D plasmático e valores de b* no dia 1. No gene DBP, o alelo C do SNP rs136359868 foi menos frequente (3,5%) do que o alelo T, enquanto que os alelos C e T do SNP rs135330728 tiveram uma frequência de 73,8 e 26,2%, respectivamente. SNPs do gene DBP foram associados com MELT na pele e valores de L* e a* em diferentes dias. No gene CAST, os alelos C e T do SNP rs109384915 tiveram a mesma frequência. O SNP rs109384915 foi associado com MFI ao dia 7 e a substituição do alelo T por C reduziu os valores de MFI e a* no dia 7 e os valores de b* no dia 1. Ao final, maiores concentrações de FAE na pele e 25-D no plasma melhoraram proteólise miofibrilar e cor de carne, enquanto as maiores concentrações de EUM e MELT na pele resultaram em uma carne mais macia com uma pior cor. Associações do loco Extension e dos SNPs no gene DBP com cor de carne parecem consequência das diferenças em 1,25-D no plasma e melanina na pele. SNP do CAST associou-se com proteólise miofibrilar e cor de carne maturada, mas não com FC. / Natural tenderization by myofibrillar proteolysis through the calpains enzymes (calcium-dependent) and discoloration by oxidation of myoglobin pigment may occur in aged meat. In cattle, the Bos indicus biological type has higher calpastatin activity (CAST, inhibitor of calpains) in muscle and melanin concentration (modulator of vitam in D3) in skin than Bos taurus. Higher melanin concentration in skin reduces photosynthesis of vitamin D3 and, subsequently, could reduce the concentrations of its metabolites 25-hydroxy-vitamin D3 (25-D) and 1,25-di-hydroxy-vitamin D3 (1,25-D; modulator of calcium) in plasma from Bos indicus cattle. In cases of higher plasma 1,25-D concentrations, an improved absorption of calcium from the diet followed by increased plasma calcium concentrations could result in enhanced activity of calpains. Furthermore, higher plasma 1,25-D concentrations could collaborate to minimize meat oxidation due to its antioxidant propriety. Then, in addition to higher CAST activity in muscle, the Bos indicus cattle could have two more disadvantages to produce tender and less oxidized meat: higher melanin concentrations in skin and lower 1,25-D concentrations in plasma. Hence, the objective of this work was to study the relationships between the concentrations of total melanin (MELT) and its fractions [pheomelanin (PHEO) and eumelanin (EUM)] in skin, vitamin D3 metabolites (25-D and 1,25-D) in plasma, plasma and muscle calcium, and tenderness [Myofibrillar Fragmentation Index (MFI) and shear force (SF)] and color (L*, a*, and b* values) in aged meat (1, 7, and 14 days) and their associations with single nucleotide polymorphisms (SNPs) in candidate genes as melanocortin-1 receptor [MC1R; rs109688013 (C/T) and rs110710422 (G/-)], vitamin D3-binding protein [DBP; rs136359868 (T/C) and rs135330728 (T/C)], and CAST [rs109384915 (T/C)]. Nellore cattle (n=86), slaughtered with 516 ± 39 kg at 24 ± 1 months, were used for genotyping and traits measurements. In skin, the EUM fraction was positively correlated with MELT than the PHEO fraction. The melanin fractions in skin were negatively correla ted. The PHEO fraction was negatively correlated with plasma 1,25-D, but not with plasma 25-D. Melanin and its fractions in skin and vitamin D3 metabolites in plasma were not correlated with plasma and muscle calcium. Nevertheless, plasma and muscle calcium were positively correlated with MFI, and L* and b* values and negatively correlated with SF and a* values. The EUM and MELT in skin were negatively correlated with SF, and a* and b* values and positively correlated with L* values, while 25-D in plasma was positively correlated with MFI, and a* and b* values and negatively correlated with L* values. The PHEO was positively correlated with MFI and negatively correlated with L*, a*, and b* values. In MC1R gene, the rs109688013 SNP allele T was fixed (100%) in the population, while the rs110710422 SNP allele G and its deletion (-) had a frequency of 97.7 and 2.3%, respectively. MC1R SNPs resulted in genotypes of the Extension locus (E/E = T/T + G/G and E/e = T/T + G/-), which was associated with plasma 1,25-D and b* values at the day 1. In DBP gene, the rs136359868 SNP allele C was less frequent (3.5%) than allele T, while rs135330728 SNP alleles C and T had a frequency of 73.8 and 26.2%, respectively. DBP SNPs were associated with MELT in skin, and L* and a* values at different days. In CAST gene, the rs109384915 SNP alleles C and T had a similar frequency. The rs109384915 SNP was associated with MFI at the day 7 and the substitution from allele T to C reduced the MFI and a* values at the day 7 and the b* values at the day 1. At last, higher skin PHEO and plasma 25-D concentrations improved the myofibrillar proteolysis and meat color, while higher skin EUM and MELT concentrations resulted in a meat with improved tenderness and worsened color. Associations of the Extension locus and polymorphisms in DBP gene with the meat color seem to be a consequence of the differences in plasma 1,25-D and skin melanin. CAST SNP is associated with myofibrillar proteolysis and meat color, but not with SF.

L'étude des parentés génétiques permet à l'anthropologie d'identifier la place du sujet au sein des différentes structures dans lesquelles il évolue : l'individu est membre d'une famille biologique, d'un groupe social et d'une population. L'application des méthodes probabilistes classiques (établies pour répondre à des problématiques de médecine légale, comme la méthode des Likelihood Ratios (LR) ou " Rapports de vraisemblance ") aux données STR issues du matériel archéologique a permis la découverte de nombreux liens de parenté, qui ensemble constituent des généalogies parfois complexes. Notre pratique prolongée de ces méthodes nous a cependant amenés à identifier certaines limites de l'interprétation des données STR, en particulier dans les cas de parentés complexes, distantes ou consanguines, ou dans des populations isolées, méconnues ou disparues. Ce travail de thèse s'attache en premier lieu à quantifier la fiabilité et l'efficacité de la méthode des LR dans quatre situations : une population moderne avec une grande diversité allélique, une population moderne avec une faible diversité allélique, une population ancienne de grande taille et une population ancienne de petite taille. Les publications récentes font usage des marqueurs plus nombreux issus des nouvelles technologies de séquençage (NGS) pour mettre en place de nouvelles stratégies de détection des parentés, basées en particulier sur l'analyse des segments chromosomiques partagés par ascendance entre les individus (segments IBD). Ces méthodes ont rendu possible l'estimation plus fiable de probabilités de parenté dans le matériel ancien. Elles sont néanmoins inadaptées à certaines situations caractéristiques de la génétique des parentés archéologiques : elles ne sont pas conçues pour fonctionner avec une seule paire isolée d'individus et reposent, comme les méthodes classiques, sur l'estimation de la diversité allélique dans la population. Nous proposons donc une quantification de la fiabilité et de l'efficacité de la méthode des segments partagés à partir de données NGS, en s'attachant à déterminer la qualité des résultats dans les différentes situations qui correspondent à des tailles de population plus ou moins importantes et à une hétérogénéité plus ou moins grande de l'échantillonnage.[...] / The study of genetic kinship allows anthropology to identify the place of an individual within which they evolve: a biological family, a social group, a population. The application of classical probabilistic methods (that were established to solve cases in legal medicine, such as Likelihood Ratios, or LR) to STR data from archaeological material has permitted the discovery of numerous parental links which together constitute genealogies both simple and complex. Our continued practice of these methods has however led us to identify limits to the interpretation of STR data, especially in cases of complex, distant or inbred kinship. The first part of the present work is constituted by the estimation of the reliability and the efficacy of the LR method in four situations: a large modern population with significant allelic diversity, a large modern population with poor allelic diversity, a large ancient population and a small ancient population. Recent publications use the more numerous markers analysed using Next generation Sequencing (NGS) to implement new strategies in the detection of kinship, especially based on the analysis of chromosome segments shared due to common ancestry (IBD "Identity-by-Descent" segments). These methods have permitted the more reliable estimation of kinship probabilities in ancient material. They are nevertheless ill-suited to certain typical situations that are characteristic of ancient DNA studies: they were not conceived to function using single pairs of isolated individuals and they depend, like classical methods, on the estimation of allelic diversity in the population. We therefore propose the quantification of the reliability and efficiency of the IBD segment method using NGS data, focusing on the estimation of the quality of results in different situations with populations of different sizes and different sets of more or less heterogeneous samples.[...]

Agaricus bisporus, le champignon de Paris, est un basidiomycète saprophytenaturellement présent dans la litière de cyprès (Cupressus macrocarpa). Il possède différentsmodes de reproduction. Pour étudier leur rôle dans la dynamique spatio-temporelle et l’évolutionde la diversité génétique au cours du temps, des dispositifs expérimentaux ont été mis en place.Dix souches sauvages d’Agaricus bisporus var. bisporus ont été sélectionnées, à partir de deuxpopulations françaises, sur leurs traits phénotypiques et génotypiques. L’étude de l’évolutionmoléculaire de leurs génomes a montré que, pour le génome mitochondrial, la mobilité desintrons de groupe I apparait comme la principale source de polymorphisme. Des taux desubstitution nucléotidique (nt) faibles ont été observés chez tous les types de séquencesmitochondriales (éléments mobiles, séquences géniques et inter géniques). Cette forteconservation, comparée avec les taux élevés de substitution nt des séquences nucléairessimilaires, contraste avec ce qui est généralement décrit dans l’évolution des séquencesfongiques. Des expériences de croisements entre sporocarpes et mycelia de souches sauvages ontété menées sur du compost, dans une chambre de culture, pour simuler l’implantation d’unepopulation naturelle. Pour les sporocarpes récoltés, les données montrent l’existence d’unphénomène parasexuel de Buller conduisant à des souches hybrides d’A. bisporus dans lachambre de culture et potentiellement dans la nature. Parallèlement, les mycelia de souchessauvages ont été introduits dans deux parcelles expérimentales de cyprès. L’analyse génotypiquedes sporocarpes récoltés la première année d’introduction n’a pas permis de mettre en évidencede souche hybride et les conditions climatiques de la seconde année n’ont pas permis d’obtenir defructification. Les dispositifs et outils mis au point doivent permettre un suivi génétique spatiotemporelde la population sur le long terme. / Agaricus bisporus, the button mushroom, is a saprophytic basidiomycete naturallyfound in cypress litter (Cupressus macrocarpa). It possesses different modes of reproduction. Tostudy their role in the spatio-temporal dynamics and in the evolution of the genetic diversity,experimental systems have been set up. Ten wild strains of Agaricus bisporus var. bisporus havebeen selected, from two french populations, on both phenotypic and genotypic traits. Themolecular evolution of their genomes has shown that, for the mitochondrial genome, group Iintron mobility was the main source of gene polymorphism. Low nucleotide (nt) substitutionrates were found in all types of mitochondrial sequences (mobile elements, genic and intergenicones). This stringent conservation of mitochondrial sequences, when compared with the high ntsubstitution rates of their nuclear counterparts, contrasts to what is widely accepted in fungalsequence evolution. Mating experiments between sporocarps and mycelia of wild strains wereconducted on compost in a room culture, to simulate the implantation of a natural population.Among the collected sporocarps, results indicate the occurrence of a parasexual Bullerphenomenon leading to hybrid strains of A. bisporus in room culture and putatively in the wild.In parallel, mycelia of the wild strains have been introduced in two experimental plots of cypress.Genotypic analysis of the sporocarps collected from these plots in the first year of introduction,failed to evidence a hybrid strain. The climatic conditions of the second year did not allowobtaining fruiting-bodies. The developed experimental systems and tools must allow a followingat the genetic level of the spatio-temporal evolution of the population.

<p>Stepska vi&scaron;nja (<em>Prunus fruticosa&nbsp;</em> Pall.)&nbsp; je autotetraploidna vrsta (FFFF, 2n = 4x = 32)&nbsp;koja se prema taksonomskom položaju svrstava u familiju&nbsp;<em> Rosaceae</em>,&nbsp; rod&nbsp; <em>Prunus</em>. Ova vrsta &nbsp;pripada sekciji&nbsp;<em> Eurocerasus</em>&nbsp; u koju se pored nje ubrajaju jo&scaron; i tre&scaron;nja (<em>Prunus avium</em>&nbsp; L.) &nbsp;i vi&scaron;nja <em>(Prunus cerasus</em>&nbsp; L.). Stepska vi&scaron;nja i tre&scaron;nja su među najranijim derivatima roda&nbsp; Prunus, dok je vi&scaron;nja nastala kroz proces prirodne hibridizacije između ove dve vrste nekoliko puta u toku istorije.&nbsp; Utvrđivanje nivoa diverziteta među biljnim&nbsp; materijalom&nbsp; koji&nbsp; se&nbsp; koristi&nbsp; u&nbsp; oplemenjivačkom radu&nbsp; je&nbsp; od&nbsp; izuzetne&nbsp; važnosti&nbsp; za unapređenje&nbsp; agronomskih svojstava bilo&nbsp; koje&nbsp; biljne&nbsp; vrste.&nbsp; Jedan od prvih koraka u istraživanju nivoa diverziteta jeste morfolo&scaron;ka karakterizacija germplazme.&nbsp; Nasuprot ovom tipu markera nalaze se molekularni markeri kojima se detektuju razlike na nivou DNK. Cilj ovog rada je bio ispitivanje inter-&nbsp; i&nbsp; intrapopulacione varijabilnosti stepske&nbsp; vi&scaron;nje (<em>P. &nbsp;fruticosa</em>) upotrebom fenotipskih, mikrosatelitskih i SNP markera, a dobijeni rezultati će olak&scaron;ati i ubrzati oplemenjivački proces tre&scaron;nje i vi&scaron;nje. Fenotipska svojstva su ispoljila visok nivo varijabilnosti prevashodno za kvantitativne markere, dok je ne&scaron;to niži stepen varijacija uočen kod kvalitativnih karaktera, a potpuno odsustvo varijabilnosti je uočeno samo u&nbsp; svojstvu prisustva lisnih žlezda. Populacije stepske vi&scaron;nje su pokazale visok nivo polimorfizma unutar i između populacija primenom mikrosatelitskih markera, a broj detektovanih alela u okviru lokusa se kretao od 2 (BPPCT022, UDP-018) do 11 (BPPCT034). Varijabilnost na nivou sekvenci DNK u okviru populacija vrste<em>&nbsp; P.&nbsp; fruticosa&nbsp;</em>je visoka, ovo je potvrđeno analizom 170256 SNP markera. Populacije stepske vi&scaron;nje na nivou sva tri tipa markera&nbsp; su pokazale visok stepen varijabilnosti kada se govori o svim analiziranim lokalitetima kao jednoj populaciji, dok je ona bila ne&scaron;to niža između jedinki na jednom lokalitetu. Bujnost kao fenotipska karakteristika pokazala je značajan nivo vezanosti za dva SNP markera Primenom generalnog linearnog modela (General Linear Model,&nbsp; GLM) u asocijativnom mapiranju genoma stepske vi&scaron;nje otkriven &nbsp;je značajan nivo vezanosti između pojedinih SNP markera i ispitivanih fenotipskih karakteristika na hromozomu 7 (S7_8740459) i na hromozomu 8 (S8_6142814). Stepska &nbsp;vi&scaron;nja kao divlji srodnik vrsta od velikog ekonomskog značaja kao &scaron;to su tre&scaron;nja i vi&scaron;nja može imati značajnu ulogu u njihovom unapređenju, a u ovom radu je potvrđeno da poseduje veliki diverzitet &scaron;to je čini jo&scaron; značajnijom i potencijalnim izvorom nove varijabilnosti.</p> / <p>European ground cherry&nbsp; <em>(Prunus fruticos</em>a&nbsp; Pall.)&nbsp; is autotetraploid species&nbsp; (FFFF, 2n = 4x = 32) and belongs to <em>Prunus genus</em> and <em>Rosaceae</em> family. It is a part of&nbsp; Eurocerasus section that also includes sweet cherry (Prunus avium&nbsp; L.) and sour cherry <em>(Prunus cerasus</em>&nbsp; L.). Sweet cherry and ground cherry are presumably early derivatives of ancestral Prunus while sour cherry arose from natural hybridization between these two species several times trough history. Determination of diversity is of great importance in every breeding program, and morphological characterization continues to be the first step for the description&nbsp; and classification of that diversity. Other available tolls for measuring diversity among germplasm are molecular markers. Aim of this research was to determine level of inter-&nbsp; and intrapopulation variability in European ground cherry<em> (P.&nbsp; fruticosa&nbsp;</em> Pall.)&nbsp; using phenotypic, SSR and SNP markers to facilitate cherry breeding. Phenotype characteristics exhibited high level of variability especially for quantitative traits, while qualitative traits had shown lower level of variability. Only presence of leaf nectaries had absence of variability; all analyzed accessions had nectaries on their leaves. Microsatellite markers confirmed high variability between and within all analyzed populations of ground cherry. Number of alleles per markers ranged from 2 (BPPCT002 and UDP-018) to 11 (BPPCT034). Analysis of 170,256 SNP markers confirmed high level of variability in DNA sequences of<em> P. fruticosa</em>. All analyzed populations of ground cherry showed overall high level of variability using all types of markers, while variability was relatively lower within each population. Association study revealed significant level of association between several traits and SNP markers. Vigor as a trait of interest showed significant association with SNP on chromosome 7 (S7_8740459) and chromosome 8 (S8_6142814). European ground cherry as one of wild relatives of economically important fruit species, such as sweet and sour cherry, holds great potential in their improvement. Its high level of diversity, revealed in this research, provides additional source of variability and makes it valuable for breeding programs.</p>