15,475 research outputs found

    Bioactive Compounds from Marine Heterobranchs

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    The natural products of heterobranch molluscs display a huge variability both in structure and in their bioactivity. Despite the considerable lack of information, it can be observed from the recent literature that this group of animals possesses an astonishing arsenal of molecules from different origins that provide the molluscs with potent chemicals that are ecologically and pharmacologically relevant. In this review, we analyze the bioactivity of more than 450 compounds from ca. 400 species of heterobranch molluscs that are useful for the snails to protect themselves in different ways and/or that may be useful to us because of their pharmacological activities. Their ecological activities include predator avoidance, toxicity, antimicrobials, antifouling, trail-following and alarm pheromones, sunscreens and UV protection, tissue regeneration, and others. The most studied ecological activity is predation avoidance, followed by toxicity. Their pharmacological activities consist of cytotoxicity and antitumoral activity; antibiotic, antiparasitic, antiviral, and anti-inflammatory activity; and activity against neurodegenerative diseases and others. The most studied pharmacological activities are cytotoxicity and anticancer activities, followed by antibiotic activity. Overall, it can be observed that heterobranch molluscs are extremely interesting in regard to the study of marine natural products in terms of both chemical ecology and biotechnology studies, providing many leads for further detailed research in these fields in the near future

    Estudo da remodelagem reversa miocárdica através da análise proteómica do miocárdio e do líquido pericárdico

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    Valve replacement remains as the standard therapeutic option for aortic stenosis patients, aiming at abolishing pressure overload and triggering myocardial reverse remodeling. However, despite the instant hemodynamic benefit, not all patients show complete regression of myocardial hypertrophy, being at higher risk for adverse outcomes, such as heart failure. The current comprehension of the biological mechanisms underlying an incomplete reverse remodeling is far from complete. Furthermore, definitive prognostic tools and ancillary therapies to improve the outcome of the patients undergoing valve replacement are missing. To help abridge these gaps, a combined myocardial (phospho)proteomics and pericardial fluid proteomics approach was followed, taking advantage of human biopsies and pericardial fluid collected during surgery and whose origin anticipated a wealth of molecular information contained therein. From over 1800 and 750 proteins identified, respectively, in the myocardium and in the pericardial fluid of aortic stenosis patients, a total of 90 dysregulated proteins were detected. Gene annotation and pathway enrichment analyses, together with discriminant analysis, are compatible with a scenario of increased pro-hypertrophic gene expression and protein synthesis, defective ubiquitinproteasome system activity, proclivity to cell death (potentially fed by complement activity and other extrinsic factors, such as death receptor activators), acute-phase response, immune system activation and fibrosis. Specific validation of some targets through immunoblot techniques and correlation with clinical data pointed to complement C3 β chain, Muscle Ring Finger protein 1 (MuRF1) and the dual-specificity Tyr-phosphorylation regulated kinase 1A (DYRK1A) as potential markers of an incomplete response. In addition, kinase prediction from phosphoproteome data suggests that the modulation of casein kinase 2, the family of IκB kinases, glycogen synthase kinase 3 and DYRK1A may help improve the outcome of patients undergoing valve replacement. Particularly, functional studies with DYRK1A+/- cardiomyocytes show that this kinase may be an important target to treat cardiac dysfunction, provided that mutant cells presented a different response to stretch and reduced ability to develop force (active tension). This study opens many avenues in post-aortic valve replacement reverse remodeling research. In the future, gain-of-function and/or loss-of-function studies with isolated cardiomyocytes or with animal models of aortic bandingdebanding will help disclose the efficacy of targeting the surrogate therapeutic targets. Besides, clinical studies in larger cohorts will bring definitive proof of complement C3, MuRF1 and DYRK1A prognostic value.A substituição da válvula aórtica continua a ser a opção terapêutica de referência para doentes com estenose aórtica e visa a eliminação da sobrecarga de pressão, desencadeando a remodelagem reversa miocárdica. Contudo, apesar do benefício hemodinâmico imediato, nem todos os pacientes apresentam regressão completa da hipertrofia do miocárdio, ficando com maior risco de eventos adversos, como a insuficiência cardíaca. Atualmente, os mecanismos biológicos subjacentes a uma remodelagem reversa incompleta ainda não são claros. Além disso, não dispomos de ferramentas de prognóstico definitivos nem de terapias auxiliares para melhorar a condição dos pacientes indicados para substituição da válvula. Para ajudar a resolver estas lacunas, uma abordagem combinada de (fosfo)proteómica e proteómica para a caracterização, respetivamente, do miocárdio e do líquido pericárdico foi seguida, tomando partido de biópsias e líquidos pericárdicos recolhidos em ambiente cirúrgico. Das mais de 1800 e 750 proteínas identificadas, respetivamente, no miocárdio e no líquido pericárdico dos pacientes com estenose aórtica, um total de 90 proteínas desreguladas foram detetadas. As análises de anotação de genes, de enriquecimento de vias celulares e discriminativa corroboram um cenário de aumento da expressão de genes pro-hipertróficos e de síntese proteica, um sistema ubiquitina-proteassoma ineficiente, uma tendência para morte celular (potencialmente acelerada pela atividade do complemento e por outros fatores extrínsecos que ativam death receptors), com ativação da resposta de fase aguda e do sistema imune, assim como da fibrose. A validação de alguns alvos específicos através de immunoblot e correlação com dados clínicos apontou para a cadeia β do complemento C3, a Muscle Ring Finger protein 1 (MuRF1) e a dual-specificity Tyr-phosphoylation regulated kinase 1A (DYRK1A) como potenciais marcadores de uma resposta incompleta. Por outro lado, a predição de cinases a partir do fosfoproteoma, sugere que a modulação da caseína cinase 2, a família de cinases do IκB, a glicogénio sintase cinase 3 e da DYRK1A pode ajudar a melhorar a condição dos pacientes indicados para intervenção. Em particular, a avaliação funcional de cardiomiócitos DYRK1A+/- mostraram que esta cinase pode ser um alvo importante para tratar a disfunção cardíaca, uma vez que os miócitos mutantes responderam de forma diferente ao estiramento e mostraram uma menor capacidade para desenvolver força (tensão ativa). Este estudo levanta várias hipóteses na investigação da remodelagem reversa. No futuro, estudos de ganho e/ou perda de função realizados em cardiomiócitos isolados ou em modelos animais de banding-debanding da aorta ajudarão a testar a eficácia de modular os potenciais alvos terapêuticos encontrados. Além disso, estudos clínicos em coortes de maior dimensão trarão conclusões definitivas quanto ao valor de prognóstico do complemento C3, MuRF1 e DYRK1A.Programa Doutoral em Biomedicin

    New functions of platelet C3G: Involvement in TPO-regulation, ischemia-induced angiogenesis and tumor metastasis

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    [ES] Las GTPasas son proteínas que regulan una gran variedad de procesos celulares, entre los que cabe destacar la proliferación, la diferenciación celular y la apoptosis. Estas proteínas alternan entre dos confirmaciones: una activa o unida a GTP y una inactiva o unida a GDP. El intercambio de GDP por GTP esta catalizado por un grupo de proteínas denominadas GEF (factores intercambiadores de nucleótidos de guanina), mientras que las proteínas GAP (proteínas activadoras de la actividad GTPasa) inhiben a la GTPasa. C3G es un GEF para varias GTPasas de la familia de Ras, principalmente de Rap1, R-Ras y TC21, y para una GTPasa de la familia de Rho, TC10. Mediante el uso de modelos animales que expresan de manera específica en plaquetas y megacariocitos o bien C3G (tgC3G), o bien una forma mutante de C3G (caracterizada por la pérdida del dominio catalítico, tgC3GCat), nuestro grupo ha demostrado la participación de C3G en la diferenciación megacariocítica, así como en la regulación de la función hemostática de las plaquetas. En concreto, las plaquetas tgC3G presentan una mayor activación y agregación plaquetaria, que se correlaciona con tiempos de sangrado significativamente inferiores en los ratones tgC3G, además de un incremento en la formación de trombos en modelos in vivo. La sobreexpresión de C3G plaquetario, también genera una alteración en la secreción de los gránulos-α, caracterizada por la retención del factor de crecimiento del endotelio vascular (VEGF) y de trombospondina- 1 (TSP-1) en el citoplasma de las plaquetas, dando lugar a un secretoma netamente proangiogénico. Como resultado de la mayor capacidad proangiogénica de las plaquetas que sobreexpresan C3G, los ratones tgC3G mostraron un crecimiento tumoral más rápido en dos modelos heterotópicos de implantación tumoral. Además, la proteína C3G plaquetaria promueve la metástasis pulmonar de células de melanoma (B16-F10). Sin embargo, la expresión transgénica de C3G no altera los recuentos plaquetarios en sangre periférica. En esta Tesis, hemos profundizado en el papel de C3G en la megacariopoyesis, en la angiogénesis inducida por isquemia y en la metástasis tumoral. Para ello, hemos desarrollado un modelo animal adicional (C3G-KO), en el cual C3G se encuentra específicamente delecionado en megacariocitos (Mk). Al igual que lo observado en ratones tgC3G, los animales C3G-KO tampoco mostraron diferencias ni en el número de Mk en médula ósea, ni en los recuentos plaquetarios en sangre periférica. Sin embargo, la deleción de C3G resultó en una mayor maduración megacariocítica in vitro cuando las médulas óseas fueron cultivas en medio enriquecido con trombopoyetina (TPO) junto con un cocktail de citocinas, sugiriendo un posible papel de C3G en una megacariopoyesis patológica. En base a esto, hemos analizamos el papel de C3G en dos modelos in vivo de megacariopoyesis patológica: la inyección de TPO y la mielosupresión inducida por 5- Fluoruracilo (5-FU). La inyección intravenosa de TPO estimula la megacariopoyesis, incrementando los niveles plaquetarios; mientras que el 5-FU induce la depleción de la médula ósea alrededor del séptimo día tas la inyección, lo que va seguido de un profundo incremento en el recuento plaquetario, proceso conocido como rebote plaquetario (platelet rebound) tras 10-15 días de tratamiento

    Deciphering Regulation in Escherichia coli: From Genes to Genomes

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    Advances in DNA sequencing have revolutionized our ability to read genomes. However, even in the most well-studied of organisms, the bacterium Escherichia coli, for ≈ 65% of promoters we remain ignorant of their regulation. Until we crack this regulatory Rosetta Stone, efforts to read and write genomes will remain haphazard. We introduce a new method, Reg-Seq, that links massively-parallel reporter assays with mass spectrometry to produce a base pair resolution dissection of more than 100 E. coli promoters in 12 growth conditions. We demonstrate that the method recapitulates known regulatory information. Then, we examine regulatory architectures for more than 80 promoters which previously had no known regulatory information. In many cases, we also identify which transcription factors mediate their regulation. This method clears a path for highly multiplexed investigations of the regulatory genome of model organisms, with the potential of moving to an array of microbes of ecological and medical relevance.</p

    Proof of Concept of Therapeutic Gene Modulation of MBNL1/2 in Myotonic Dystrophy

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    La distrofia miotónica tipo 1 es una enfermedad genética rara multisistémica que afecta a 1 de cada 3000-8000 personas. La causa molecular de la enfermedad proviene de repeticiones tóxicas “CTG” en el gen DMPK (DM Protein Kinase). Tras la transcripción, estas repeticiones forman una estructura de horquilla que se une con alta afinidad a la familia de proteínas MBNL (Muscleblind-like) que agota su función de regulación de la poliadenilación y el splicing alternativo postranscripcional en numerosos transcritos. La pérdida de función de MBNL provoca una cascada de efectos posteriores, que eventualmente conducen a síntomas clínicos que incluyen miotonía, debilidad y atrofia muscular, cataratas, disfunción cardíaca y trastorno cognitivo. La restauración de la función de la proteína MBNL es clave para aliviar los síntomas debilitantes de esta enfermedad. Se han utilizado oligonucleótidos antisentido (AON) para apuntar a las repeticiones de DMPK y liberar MBNL del secuestro, lo que da como resultado resultados terapéuticos prometedores en modelos celulares y animales de la enfermedad. Otro factor que interviene en la pérdida de función de las proteínas MBNL son los miRNAs que regulan su traducción. Aquí se muestra el uso de AON dirigidos a la actividad de miR-23b y miR-218, que se ha demostrado previamente que regulan directamente MBNL1 y MBNL2. Estos antimiRs recibieron modificaciones FANA para aumentar su entrega en las células y reducir la toxicidad. También se probaron los AON, denominados blockmiRs, que se unen de manera complementaria a los sitios de unión confirmados de miR-23b y miR-218 en los 3'-UTR de las transcripciones de MBNL1 y MBNL2. De esta manera, los miRNAs no pueden unirse y regular la traducción de MBNL, lo que aumenta la cantidad de proteína MBNL producida en una célula deficiente. Aquí se propone el uso de AON de nuevo diseño dirigidos a la actividad de miR-23b y miR-218 para regular MBNL1 y MBNL2 a través de (1) exploración del bloqueo de miRNA a través de FANA-antimiR AON in vitro, (2) exploración del bloqueo del sitio de unión de miRNA a través de la estrategia blockmiR in vitro e in vivo con el uso de modificaciones químicas de LNA, y (3) mejora de la química de la estrategia blockmiR mediante el uso de tecnología de péptidos de penetración celular in vitro e in vivo.Myotonic Dystrophy Type 1 is a multi-systemic rare genetic disease affecting 1 in 3000-8000 people. The molecular cause of the disease stems from toxic “CTG” repetitions in the DMPK (DM Protein Kinase) gene. Upon transcription, these repetitions form a hairpin structure that binds with high affinity to the MBNL (Muscleblind-like) family of proteins depleting their function of post-transcriptional alternative splicing and polyadenylation regulation on numerous transcripts. MBNL loss-of-function causes a cascade of downstream effects, which eventually lead to clinical symptoms including myotonia, muscle weakness and atrophy, cataracts, cardiac dysfunction, and cognitive disorder. The restoration of MBNL protein function is key to relieving the debilitating symptoms of this disease. Antisense oligonucleotides (AONs) have been used to target the DMPK repeats and release MBNL from sequestration resulting in promising therapeutic results in cellular and animal models of the disease. Another factor playing a role in the loss-of-function of MBNL proteins are the miRNAs that regulate their translation. Here is shown the use of AONs targeting miR-23b and miR-218 activity, which have been previously shown to directly regulate MBNL1 and MBNL2. These antimiRs were given FANA modifications to increase their delivery in cells and lower toxicity. Also tested are AONs, termed blockmiRs, that complementary bind to the confirmed binding sites of miR-23b and miR-218 in the 3’-UTRs of MBNL1 and MBNL2 transcripts. In this way, the miRNAs are unable to bind and regulate the translation of MBNL thereby augmenting the amount of MBNL protein made in an otherwise deficient cell. Proposed here is the use of newly designed AONs targeting miR-23b and miR-218 activity in order to regulate MBNL1 and MBNL2 through (1) exploration of miRNA blocking through FANA-antimiR AONs in vitro, (2) exploration of miRNA binding site blocking through blockmiR strategy in vitro and in vivo with the use of LNA chemical modifications, and (3) improvement of the chemistry of the blockmiR strategy through the use of cell penetrating peptide technology in vitro and in vivo

    Tombusvirids Avoid and Exploit a Plant Exoribonuclease

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    Tombusviridae is a family of plus-strand RNA plant viruses that contain single-stranded RNA genomes with no 5' cap or 3' poly(A) tail. The 5' cap is an essential post-transcriptional modification that increases the stability of mRNA molecules, by protecting them from 5'-to-3' exoribonuclease decay. The lack of this modification in this virus family raised the question of how these viruses protect their vulnerable genomic 5' ends from nuclease attack during infections. Carnation Italian ringspot virus (CIRV) from the genus Tombusvirus, family Tombusviridae, has a plus-strand RNA genome with a structured 5' untranslated region that I hypothesized could serve as a protective substitute for the 5' cap. Results from my in vitro and in vivo studies with CIRV showed that the higher-order RNA structure at the 5' end of its genome was able to effectively prevent access of a 5'-to-3' exoribonuclease (Xrn), thereby protecting it from being degraded by Xrn during infections. In a second related study, I investigated a small viral RNA (svRNA) that accumulated in infections with another member of the family Tombusviridae, Tobacco necrosis virus-D (TNV-D; genus Betanecrovirus). In this case, I hypothesized that the svRNA represented a stable degradation product that could be functionally relevant to successful TNV-D infections. Through in vitro and in vivo analyses of TNV-D, I determined that the svRNA was indeed generated from incomplete digestion of the TNV-D genome by Xrn, and that its accumulation was beneficial in infections. Collectively, these findings extend and broaden our knowledge of the roles of novel viral RNA structures in facilitating successful viral infections by either evading (CIRV) or exploiting (TNV-D) the activity of the cellular exoribonuclease, Xrn

    An Overview of the Mechanisms Involved in Coffee-Hemileia vastatrix Interactions: Plant and Pathogen Perspectives

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    Coffee is one of the most consumed beverages in the world. It is also one of the most globally traded commodities. Coffee leaf rust (CLR), caused by the biotrophic fungus Hemileia vastatrix, is the most important disease affecting Arabica coffee growing worldwide, leading to significant yield losses if no control measures are applied. A deep understanding of the complex mechanisms involved in coffee-H. vastatrix interactions, such as the pathogen variability and the mechanisms governing plant resistance and susceptibility, is required to breed efficiently for durable resistance and design new approaches for crop protection. Here we summarize our current understanding across multiple areas related to pathogen infection, variability and candidate effectors, breeding for disease resistance, and the various components of the coffee immune system, by reviewing a comprehensive body of research on CLR and the advances recently made. We also update information about the defense responses activated by the application of plant resistance inducers, a promising alternative to fungicides in the control of CLR. Moreover, we identify and discuss future directions for further researchinfo:eu-repo/semantics/publishedVersio

    Contribution of non-canonical DNA G-quadruplex structures to premature ageing

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    Previous studies have identified Cockayne Syndrome B (CSB) as a helicase that can resolve non-canonical DNA structures, called G-quadruplexes (G4s). The aim of this study is to investigate the properties of CSB as a G4-binder and -resolvase, and examine the correlation between the G4-helicase activity of CSB and premature ageing phenotype observed in CSB-deficient cells. Accordingly, the recombinant CSB full-length protein (FL) and its helicase- “like" domain (HD) were respectively expressed from insect and bacterial cells, and their resolvase and binding activities were tested over a large panel of DNA substrates. Native gel analysis and biophysical characterisations revealed that ribosomal DNA (rDNA) sequences, that typically act as CSB substrate, can form intermolecular G4s. We discovered that intermolecular G4s were strongly bound by CSB with picomolar affinity, whilst negligible binding to intramolecular G4s was observed. In vitro and cellular data demonstrated that G4-ligands can compete with CSB for binding to intermolecular rDNA G4, which results in CSB being displaced off the nucleoli of cells upon treatment with G4-ligands. Immunostaining with the selective G4-antibody BG4 revealed a lack of BG4-staining in the nucleoli of CSB-deficient cells after exogenous expression of recombinant CSB, further corroborating the hypothesis that CSB can bind intermolecular rDNA G4s in the nucleoli and compete with BG4 for the binding of such DNA-substrate. The work presented in this thesis allowed us to observe that (I) intermolecular G4s are likely to form from long-range distant rDNA sequences within the nucleoli of cells, and (II) CSB specifically binds and resolves these structures. Our results provide the first evidence of an endogenous protein that specifically interacts with intermolecular G4s, suggesting potential biological significance of these structures. The biological relevance of intermolecular rDNA G4s could be key in rare genetic disorders like Cockayne Syndrome, where senescence and premature ageing is observed when CSB is functionally mutated.Open Acces

    Optimizing transcriptomics to study the evolutionary effect of FOXP2

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    The field of genomics was established with the sequencing of the human genome, a pivotal achievement that has allowed us to address various questions in biology from a unique perspective. One question in particular, that of the evolution of human speech, has gripped philosophers, evolutionary biologists, and now genomicists. However, little is known of the genetic basis that allowed humans to evolve the ability to speak. Of the few genes implicated in human speech, one of the most studied is FOXP2, which encodes for the transcription factor Forkhead box protein P2 (FOXP2). FOXP2 is essential for proper speech development and two mutations in the human lineage are believed to have contributed to the evolution of human speech. To address the effect of FOXP2 and investigate its evolutionary contribution to human speech, one can utilize the power of genomics, more specifically gene expression analysis via ribonucleic acid sequencing (RNA-seq). To this end, I first contributed in developing mcSCRB-seq, a highly sensitive, powerful, and efficient single cell RNA-seq (scRNA-seq) protocol. Previously having emerged as a central method for studying cellular heterogeneity and identifying cellular processes, scRNA-seq was a powerful genomic tool but lacked the sensitivity and cost-efficiency of more established protocols. By systematically evaluating each step of the process, I helped find that the addition of polyethylene glycol increased sensitivity by enhancing the cDNA synthesis reaction. This, along with other optimizations resulted in developing a sensitive and flexible protocol that is cost-efficient and ideal in many research settings. A primary motivation driving the extensive optimizations surrounding single cell transcriptomics has been the generation of cellular atlases, which aim to identify and characterize all of the cells in an organism. As such efforts are carried out in a variety of research groups using a number of different RNA-seq protocols, I contributed in an effort to benchmark and standardize scRNA-seq methods. This not only identified methods which may be ideal for the purpose of cell atlas creation, but also highlighted optimizations that could be integrated into existing protocols. Using mcSCRB-seq as a foundation as well as the findings from the scRNA-seq benchmarking, I helped develop prime-seq, a sensitive, robust, and most importantly, affordable bulk RNA-seq protocol. Bulk RNA-seq was frequently overlooked during the efforts to optimize and establish single-cell techniques, even though the method is still extensively used in analyzing gene expression. Introducing early barcoding and reducing library generation costs kept prime-seq cost-efficient, but basing it off of single-cell methods ensured that it would be a sensitive and powerful technique. I helped verify this by benchmarking it against TruSeq generated data and then helped test the robustness by generating prime-seq libraries from over seventeen species. These optimizations resulted in a final protocol that is well suited for investigating gene expression in comprehensive and high-throughput studies. Finally, I utilized prime-seq in order to develop a comprehensive gene expression atlas to study the function of FOXP2 and its role in speech evolution. I used previously generated mouse models: a knockout model containing one non-functional Foxp2 allele and a humanized model, which has a variant Foxp2 allele with two human-specific mutations. To study the effect globally across the mouse, I helped harvest eighteen tissues which were previously identified to express FOXP2. By then comparing the mouse models to wild-type mice, I helped highlight the importance of FOXP2 within lung development and the importance of the human variant allele in the brain. Both mcSCRB-seq and prime-seq have already been used and published in numerous studies to address a variety of biological and biomedical questions. Additionally, my work on FOXP2 not only provides a thorough expression atlas, but also provides a detailed and cost-efficient plan for undertaking a similar study on other genes of interest. Lastly, the studies on FOXP2 done within this work, lay the foundation for future studies investigating the role of FOXP2 in modulating learning behavior, and thereby affecting human speech

    Unraveling the effect of sex on human genetic architecture

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    Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes, amongst other factors. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides the genome with a distinct hormonal milieu, differential gene expression, and environmental pressures arising from gender societal roles. This thus poses the possibility of observing gene by sex (GxS) interactions between the sexes that may contribute to some of the phenotypic differences observed. In recent years, there has been growing evidence of GxS, with common genetic variation presenting different effects on males and females. These studies have however been limited in regards to the number of traits studied and/or statistical power. Understanding sex differences in genetic architecture is of great importance as this could lead to improved understanding of potential differences in underlying biological pathways and disease etiology between the sexes and in turn help inform personalised treatments and precision medicine. In this thesis we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We further investigated whether sex-agnostic (non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we studied the potential functional role of sex differences in genetic architecture through sex biased expression quantitative trait loci (eQTL) and gene-level analyses. Overall, this study marks a broad examination of the genetics of sex differences. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Furthermore, our results suggest the need to consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms
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