Letteratura scientifica selezionata sul tema "Causative variants"
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Articoli di riviste sul tema "Causative variants"
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Pareja, Fresia, Ryan N. Ptashkin, David N. Brown, Fatemeh Derakhshan, Pier Selenica, Edaise M. da Silva, Andrea M. Gazzo et al. "Cancer-Causative Mutations Occurring in Early Embryogenesis". Cancer Discovery 12, n. 4 (23 dicembre 2021): 949–57. http://dx.doi.org/10.1158/2159-8290.cd-21-1110.
Testo completoAbstract (sommario):
Abstract Mosaic mutations in normal tissues can occur early in embryogenesis and be associated with hereditary cancer syndromes when affecting cancer susceptibility genes (CSG). Their contribution to apparently sporadic cancers is currently unknown. Analysis of paired tumor/blood sequencing data of 35,310 patients with cancer revealed 36 pathogenic mosaic variants affecting CSGs, most of which were not detected by prior clinical genetic testing. These CSG mosaic variants were consistently detected at varying variant allelic fractions in microdissected normal tissues (n = 48) from distinct embryonic lineages in all individuals tested, indicating their early embryonic origin, likely prior to gastrulation, and likely asymmetrical propagation. Tumor-specific biallelic inactivation of the CSG affected by a mosaic variant was observed in 91.7% (33/36) of cases, and tumors displayed the hallmark pathologic and/or genomic features of inactivation of the respective CSGs, establishing a causal link between CSG mosaic variants arising in early embryogenesis and the development of apparently sporadic cancers. Significance: Here, we demonstrate that mosaic variants in CSGs arising in early embryogenesis contribute to the oncogenesis of seemingly sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may affect therapeutic decisions as well as prophylactic measures for patients and their offspring. See related commentary by Liggett and Sankaran, p. 889. This article is highlighted in the In This Issue feature, p. 873
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Shakil, Muhammad, Abida Akbar, Nazish Mahmood Aisha, Intzar Hussain, Muhammad Ikram Ullah, Muhammad Atif, Haiba Kaul et al. "Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families". Genes 13, n. 3 (12 marzo 2022): 503. http://dx.doi.org/10.3390/genes13030503.
Testo completoAbstract (sommario):
Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA.
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Thanikachalam, Saradadevi, Elizabeth Hodapp, Ta C. Chang, Dayna Morel Swols, Filiz B. Cengiz, Shengru Guo, Mohammad F. Zafeer et al. "Spectrum of Genetic Variants Associated with Anterior Segment Dysgenesis in South Florida". Genes 11, n. 4 (26 marzo 2020): 350. http://dx.doi.org/10.3390/genes11040350.
Testo completoAbstract (sommario):
Anterior segment dysgenesis (ASD) comprises a wide spectrum of developmental conditions affecting the cornea, iris, and lens, which may be associated with abnormalities of other organs. To identify disease-causing variants, we performed exome sequencing in 24 South Florida families with ASD. We identified 12 likely causative variants in 10 families (42%), including single nucleotide or small insertion–deletion variants in B3GLCT, BMP4, CYP1B1, FOXC1, FOXE3, GJA1, PXDN, and TP63, and a large copy number variant involving PAX6. Four variants were novel. Each variant was detected only in one family. Likely causative variants were detected in 1 out of 7 black and 9 out of 17 white families. In conclusion, exome sequencing for ASD allows us to identify a wide spectrum of rare DNA variants in South Florida. Further studies will explore missing variants, especially in the black communities.
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Bengani, Hemant, Detelina Grozeva, Lambert Moyon, Shipra Bhatia, Susana R. Louros, Jilly Hope, Adam Jackson et al. "Identification and functional modelling of plausibly causative cis-regulatory variants in a highly-selected cohort with X-linked intellectual disability". PLOS ONE 16, n. 8 (13 agosto 2021): e0256181. http://dx.doi.org/10.1371/journal.pone.0256181.
Testo completoAbstract (sommario):
Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.
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Wuyun, Saina. "Causative alternation in Zuo Tradition". Language and Linguistics / 語言暨語言學 25, n. 1 (2 gennaio 2024): 123–61. http://dx.doi.org/10.1075/lali.00151.wuy.
Testo completoAbstract (sommario):
Abstract This study examines the different variants of causative alternation in Zuo Tradition (左傳), an archaic Chinese narrative history from the Pre-Qin period. It is found that denominal verbs, unergative verbs, and “pure” unaccusative verbs participate actively in the alternation, and that the causative variant bears a complex relation with the agentive and putative variants; this causes problems for previous analyses. This paper proposes a two-step build-up of eventuality for causative alternation in archaic Chinese. Specifically, I propose that verbs in archaic Chinese are monadic and select only one argument. The merger of the verb with this argument is the realization of its eventuality conceptualized in the Lexicon; any further merger is determined by the eventuality composed by different light verbs in syntax. The uninitiated light verb is a placeholder with an empty argument. A specific light verb value is determined by the eventuality that is sent to the syntactic structure. Thus, the difference between all variants in causative alternation witnessed in Zuo Tradition lies in the different eventualities which they introduce into the syntactic configuration.
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Di Taranto, Maria Donata, e Giuliana Fortunato. "Genetic Heterogeneity of Familial Hypercholesterolemia: Repercussions for Molecular Diagnosis". International Journal of Molecular Sciences 24, n. 4 (6 febbraio 2023): 3224. http://dx.doi.org/10.3390/ijms24043224.
Testo completoAbstract (sommario):
Genetics of Familial Hypercholesterolemia (FH) is ascribable to pathogenic variants in genes encoding proteins leading to an impaired LDL uptake by the LDL receptor (LDLR). Two forms of the disease are possible, heterozygous (HeFH) and homozygous (HoFH), caused by one or two pathogenic variants, respectively, in the three main genes that are responsible for the autosomal dominant disease: LDLR, APOB and PCSK9 genes. The HeFH is the most common genetic disease in humans, being the prevalence about 1:300. Variants in the LDLRAP1 gene causes FH with a recessive inheritance and a specific APOE variant was described as causative of FH, contributing to increase FH genetic heterogeneity. In addition, variants in genes causing other dyslipidemias showing phenotypes overlapping with FH may mimic FH in patients without causative variants (FH-phenocopies; ABCG5, ABCG8, CYP27A1 and LIPA genes) or act as phenotype modifiers in patients with a pathogenic variant in a causative gene. The presence of several common variants was also considered a genetic basis of FH and several polygenic risk scores (PRS) have been described. The presence of a variant in modifier genes or high PRS in HeFH further exacerbates the phenotype, partially justifying its variability among patients. This review aims to report the updates on the genetic and molecular bases of FH with their implication for molecular diagnosis.
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Thongnak, Chuphong, Areerat Hnoonual, Duangkamol Tangviriyapaiboon, Suchaya Silvilairat, Apichaya Puangpetch, Ekawat Pasomsub, Wasun Chantratita, Pornprot Limprasert e Chonlaphat Sukasem. "Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder". International Journal of Genomics 2018 (2018): 1–7. http://dx.doi.org/10.1155/2018/8231547.
Testo completoAbstract (sommario):
Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.
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Moyon, Lambert, Camille Berthelot, Alexandra Louis, Nga Thi Thuy Nguyen e Hugues Roest Crollius. "Classification of non-coding variants with high pathogenic impact". PLOS Genetics 18, n. 4 (29 aprile 2022): e1010191. http://dx.doi.org/10.1371/journal.pgen.1010191.
Testo completoAbstract (sommario):
Whole genome sequencing is increasingly used to diagnose medical conditions of genetic origin. While both coding and non-coding DNA variants contribute to a wide range of diseases, most patients who receive a WGS-based diagnosis today harbour a protein-coding mutation. Functional interpretation and prioritization of non-coding variants represents a persistent challenge, and disease-causing non-coding variants remain largely unidentified. Depending on the disease, WGS fails to identify a candidate variant in 20–80% of patients, severely limiting the usefulness of sequencing for personalised medicine. Here we present FINSURF, a machine-learning approach to predict the functional impact of non-coding variants in regulatory regions. FINSURF outperforms state-of-the-art methods, owing in particular to optimized control variants selection during training. In addition to ranking candidate variants, FINSURF breaks down the score for each variant into contributions from individual annotations, facilitating the evaluation of their functional relevance. We applied FINSURF to a diverse set of 30 diseases with described causative non-coding mutations, and correctly identified the disease-causative non-coding variant within the ten top hits in 22 cases. FINSURF is implemented as an online server to as well as custom browser tracks, and provides a quick and efficient solution to prioritize candidate non-coding variants in realistic clinical settings.
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Thomas, Laurent F., Takaya Saito e Pål Sætrom. "Inferring causative variants in microRNA target sites". Nucleic Acids Research 39, n. 16 (21 giugno 2011): e109-e109. http://dx.doi.org/10.1093/nar/gkr414.
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Boudellioua, Imane, Rozaimi B. Mahamad Razali, Maxat Kulmanov, Yasmeen Hashish, Vladimir B. Bajic, Eva Goncalves-Serra, Nadia Schoenmakers, Georgios V. Gkoutos, Paul N. Schofield e Robert Hoehndorf. "Semantic prioritization of novel causative genomic variants". PLOS Computational Biology 13, n. 4 (17 aprile 2017): e1005500. http://dx.doi.org/10.1371/journal.pcbi.1005500.
Testo completoTesi sul tema "Causative variants"
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Boulding, Hannah. "Identifying causative elements within structural variants associated with developmental disorders". Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:d9af47cc-1c91-4a66-a6ac-86655f1ff375.
Testo completoAbstract (sommario):
It has been well established that copy number variation contributes substantially to genetic variation within human populations. However, the extent to which de novo and inherited copy number variants (CNVs) underlie human disease is not well known. In this thesis, I investigate the role of de novo and inherited CNVs in a wide range of developmental abnormalities. First, I compare disease associated and apparently benign CNVs for structural differences, with the aim of identifying distinguishing features of disease causing CNVs. I identified significant enrichments of protein-coding genes, protein-coding genes associated with disease in OMIM and miRNAs amongst disease associated disease. Conversely, inherited CNVs observed in healthy individuals show depletions of these features. Following this, I employ functional enrichment approaches to identify the copy number variable genes within these de novo CNVs that contribute to the patient’s developmental abnormalities. I predict candidate genes for 143 different developmental abnormalities, with 65% of the candidate genes not having been previously associated with disease in OMIM. Through examining the distribution of these candidate genes within the patient’s CNVs, I found evidence of extensive pleiotropy and epistasis as well as a small number of simple additive effects. Finally, I extend my analyses to examine the role of inherited CNVs as the underlying cause of human developmental disorders. I implicate inherited CNVs and their overlapping copy number variable genes in the underlying causes of 45 human developmental abnormalities. Additionally, I re-examine the patients possessing both de novo CNVs and inherited CNVs using functional enrichment analyses. I reveal significant enrichments for a greater number of human developmental abnormalities when combining both the de novo and inherited CNVs, suggesting it is de novo mutations in combination with the inherited genomic background that are responsible for many instances of human developmental abnormalities.
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Campbell, Caitlin. "Detection of Causative Variants Using Multigene Panels in a Pediatric Population with Epilepsy". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427812624.
Testo completo
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Buote, Caroline. "Application clinique du séquençage de l'exome pour le diagnostic moléculaire des syndromes polymalformatifs". Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6941.
Testo completoAbstract (sommario):
INTRODUCTION : Les syndromes polymalformatifs constituent un large groupe de maladies génétiques dont l'hétérogénéité limite notre capacité à identifier le gène causal à l’aide des investigations conventionnelles. Le séquençage de l'exome en clinique offre une solution à cette limitation et est maintenant disponible en recherche ou dans quelques laboratoires cliniques aux États-Unis. L'utilisation systématique du séquençage de l'exome reste encore entravée par notre capacité à gérer les trouvailles accidentelles et à prédire efficacement le ou les changements causals à partir de plusieurs milliers de variants. Ainsi, pour faciliter l'analyse de l'exome et accélérer l'implémentation du séquençage de l'exome en clinique, nous avons développé, et récemment publié à ce sujet, un logiciel nommé PhenoVar. Celui-ci intègre les données génotypiques et phénotypiques, puis suggère à l’utilisateur une courte liste priorisée de diagnostics potentiels pour révision. Nous présentons ici les données préliminaires de la validation de PhenoVar chez des patients atteints de syndromes polymalformatifs indéterminés, en comparaison à l'analyse bio-informatique standard.
MÉTHODE : Un total de 27 patients atteints de syndromes polymalformatifs d'étiologie génétique probable a été accepté pour le séquençage de l'exome. Un résultat normal a été obtenu pour chaque patient lors d’une analyse d'hybridation génomique comparative sur micropuce et reste sans diagnostic clair après le test de quelques gènes susceptibles par séquençage Sanger. À ce jour, nous avons réalisé le séquençage de 22 patients. Un médecin généticien a effectué l'analyse de ces patients utilisant PhenoVar, en parallèle à l'analyse standard réalisée par l'équipe de bio-informatique.
RÉSULTATS : En moyenne, PhenoVar a réduit le nombre de diagnostics potentiels à réviser de façon manuelle à 20 par patient, en comparaison à 64 pour l'analyse bio- informatique conventionnelle. Nous avons obtenu un rendement diagnostique global de 50% (11/22) et de 45% avec PhenoVar. Neuf fois sur onze, le bon diagnostic s’est retrouvé dans les dix premiers diagnostics de la liste de PhenoVar. Nous avons aussi identifié une variation pathologique dans BRCA2, trouvaille accidentelle réalisée durant l’analyse conventionnelle et remise au patient avec son consentement. L’outil PhenoVar permet de masquer ce type de diagnostics sans lien avec la présentation clinique. La dépendance à l’égard des bases de données s’est avérée être une limite de notre approche.
CONCLUSION : Nos résultats préliminaires suggèrent que le séquençage de l'exome combiné avec PhenoVar, en utilisant une approche axée sur le phénotype, conduit à un rendement diagnostique similaire à l'analyse bio-informatique standard et réduit le nombre de diagnostics à réviser. Comme il peut être utilisé directement par les médecins généticiens, ce logiciel pourrait faciliter l'utilisation de routine du séquençage de l'exome dans un cadre clinique.BACKGROUND : Polymalformation syndromes consist in a large group of heterogeneous genetic disorders, for which our ability to identify the causative gene using conventional investigations remains limited. Exome sequencing offers a solution and is now available either on a research basis or in few USA clinical laboratories. Routine utilization of exome sequencing is still hindered by our capacity to manage accidental findings and to predict effectively the causative change(s) out of several thousands of variants. To facilitate exome analysis and accelerate implementation of exome sequencing in clinical practice, we have developed and recently published a software named PhenoVar. This software integrates the patient’s phenotype to the genotype data and suggests to the physician-user a short list of prioritized potential diagnoses for review. Here, we present the preliminary results of PhenoVar validation in patients affected with an undetermined polymalformation syndrome, in comparison to standard bioinformatics analysis. METHODS : A total of 27 patients with polymalformative syndromes of likely genetic etiology were accepted for exome sequencing. Each patient has a normal CGH array and remains without a clear diagnosis after Sanger sequencing-based gene tests. To date, we completed the sequencing of 22 patients. A medical geneticist performed the analysis on these patients using PhenoVar, in parallel of the standard analysis done by the bioinformatics team. RESULTS : On average, PhenoVar reduced the number of potential diagnoses for manual review to 20 per patient in comparison to 64, for standard bioinformatics analysis. We obtained a global diagnostic yield of 50% (11/22) and a yield of 45% with PhenoVar. Nine times out of eleven, the correct diagnosis was found in the top ten diagnoses of the PhenoVar’s list. We also identified a pathological variant in BRCA2, accidental finding made during the conventional analysis and given to the patient who provided consent. PhenoVar allows hiding such diagnoses unrelated to the clinical presentation. Dependency on central databases has proven to be a limitation of our approach. CONCLUSION : Our preliminary results suggests that exome sequencing combined with PhenoVar, using a phenotype-driven approach, led to a similar diagnostic yield than standard bioinformatics analysis and reduced the number of diagnoses to review. Since it can be used directly by medical geneticists, this software could facilitate routine utilization of exome sequencing in clinical practice.
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Wang, Wei. "Establishment of Highly Sensitive Monitoring System of Causative Agents in Acute Respiratory Infection in Children and Emergence of New Variants and of Epidemics in Shanghai, China". Paris 7, 2010. http://www.theses.fr/2010PA077248.
Testo completoAbstract (sommario):
Les infections aiguës des voies respiratoire inférieures (ALRI) sont un problème persistant et dominant de santé publique. De nombreux virus peuvent causer une ALRI, y compris le virus respiratoire syncitial, le virus de la grippe, le virus parainfluenza, le rhinovirus, l'enterovirus, l'adénovirus et le coronavirus. Depuis l'épidémie de SRAS en 2004 et les épidémies récentes de grippe aviaire H5N1 hautement pathogène, la transmission des virus zoonotiques à l'homme pose un problème majeur de santé publique, car les contacts rapprochés entre l'animal et l'homme ou entre les hommes faciliteraient le réassortiment et la recombinaison entre les virus pour générer des nouveaux virus qui pourraient passer la barrière d'espèce. L'introduction de ces nouveaux virus dans la population immunologiquement naïve pourrait être à l'origine d'épidémies ou de pandémies. . Par ailleurs, de nouveaux virus comme le métapneumovirus humain, les coronavirus humains NL63 et HKU1, et le bocavirus humain, ont été identifiés grâce au développement des nouvelles techniques moléculaires. Toutes ces approches ont changé le profil étiologique des ALRI. Pour mieux identifier les causes d'épidémies, il est nécessaire de surveiller la distribution et l'évolution génétique des virus respiratoires. L'objectif de ce travail a été dicté en priorité par la nécessité de développer des méthodes rapides, spécifiques et sensibles de diagnostic pouvant détecter non seulement des pathogènes viraux importants mais également de nombreuses co-infections virales. Les objectifs de ce travail étaient de développer différentes techniques moléculaires multiplexées et de mettre en place une plateforme de diagnostic des virus respiratoires. La stratégie a été de développer de nouvelles techniques en rapport avec les types de virus à détecter: (1) virus prioritaires comme la grippe aviaire H5N1 ou le virus pandémique SOI-H1N1v, détectés par RT-PCR en temps réel et multiplexée; (2) virus à haute prévalence de circulation dans la population possédant une diversité génétique élevée, détectés par RT-PCR multiplexée ; virus rares et émergents, détectés et étudiés par micropuce ADN et séquençage à haut-débitAcute respiratory infections (ARIs) are one persistent and Worldwide problem to public health and the leading cause of morbidity and mortality in developing countries. In China, nearly 21 million cases occur every year [1]. Numerous viruses can cause ALRI, including respiratory syncitial virus, influenza virus, parainfluenza virus, rhinovirus, adenovirus and coronavirus [2-12]. Since the outbreak of SARS in 2004 and the recent epidemics of highly pathogenic avian influenza H5N1 virus in China [13-15] as well as in other countries of Southeast Asia, the transmission of zoonotic viruses from animals to human has become a big concern to public health because the increasing close contacts of animal-human and human-human would largely facilitate the reassortment and recombination of viruses to generate new viruses which could cross the species barrier. The introduction of new viruses to immune naïve population would cause epidemics or pandemics. Meanwhile, new viruses like human metapneumovirus, human coronaviruses NL63 and HKU1, and human bocavirus, were identified as the result of development of new molecular techniques. All these approaches have largely changed the etiological profile in ARI. To better react in case of epidemics, it is necessary to monitor the distribution and the genetic evolution of respiratory viruses. Sustained global surveillance project was required to improve the capacity in many developing countries to detect endemic, epidemic and newly emerging respiratory pathogens [16]. To set up such project, reliable and standardized diagnostic methods were requested. With sequencing and phylogenetic analysis, the project could identify a wide variety of agents, to differentiate highly pathogenic viruses from less virulent seasonal respiratory viruses and to identify new emerging viruses. Meanwhile, the epidemiological and etiological profile of ARI should be thoroughly studied to describe the background and set up a baseline for epidemic alert. In 2006, the project "Surveillance and Investigation of Endemic Situations in South-East Asia (SISEA)" was implemented (http://www. Hku. Hk/respari/research_07. Htm), which supported my PhD work. Shanghai, as the biggest metropolis of China, is an important center for population migration and with distinct four seasons including very cold winter
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Jourdain, Jeanlin. "Détection et caractérisation de variants génétiques affectant la fertilité ou la durée de gestation chez les bovins en valorisant des bases de données populationnelles". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASB028.
Testo completoAbstract (sommario):
La capacité des animaux à se reproduire est un point-clé de la gestion des troupeaux qui permet l'induction de la lactation et la naissance de veaux destinés à la vente ou au renouvellement. Du fait d'une sélection longtemps axée sur les caractères de production ces 80 dernières années, la fertilité des bovins a nettement diminué. L'objectif de ma thèse était d'exploiter les grandes bases de données françaises - constituées par l'enregistrement de 7 millions de naissances annuelles, des informations de suivi et de performances de ces animaux, complétées par 2 millions de génotypes sur puce à SNP et par les séquences de génomes complets de 5000 taureaux - pour identifier des loci influençant différentes facettes de la fertilité des mâles, des femelles et des durées de gestation. Ainsi après avoir développé une méthode de cartographie basée sur l'étude du déséquilibre de liaison entre marqueurs de chromosomes différents dans de grandes familles, 12 réarrangements interchromosomiques ont été identifiés. Ils affectent à la fois la fertilité des taureaux porteurs, celle de leurs filles et divers traits de santé. Une vingtaine de loci récessifs ont aussi été révélés en conduisant des approches cas/contrôles sur des groupes d'animaux aux phénotypes contrastés, impactant fortement la fertilité des mâles ou des femelles. Les centaines de milliers d'accouplements entre animaux génotypés ont permis d'étudier les interactions des génomes parentaux sur les résultats des inséminations et d'initier des travaux sur la compatibilité entre animaux. Enfin, des travaux sur la durée de gestation dans 16 races françaises ont complété les connaissances sur l'héritabilité et la variabilité de ce caractère et de décrire les risques associés à une sélection pour des gestations plus courtes. L'ensemble de ces résultats montrent que le bovin peut être utilisé comme modèle pour la recherche en génétique grâce aux données générées en routine en élevage. Ils doivent pouvoir être utilisés en sélection génétique pour l'amélioration de la fertilité des animaux, qui participe à la durabilité de l'élevage bovinAbstract: The ability of animals to reproduce is a key factor in herd management, leading to the induction of lactation and the birth of calves for the market or for replacement. Over the past 80 years, cattle fertility has declined sharply as a result of selection that has long focused on production traits. The aim of my thesis was to exploit the large French databases - consisting of 7 million births per year, traceability, and performance information on these animals, supplemented by 2 million genotypes on SNP arrays and the sequences of complete genome of 5,000 bulls - to identify loci influencing different aspects of male and female fertility and gestation length. By developing a mapping method based on the study of linkage disequilibrium between markers from different chromosomes in large families, 12 interchromosomal rearrangements were identified. They affect the fertility of carrier sires, their daughters and various fitness traits. Some twenty recessive loci have also been revealed by conducting case/control approaches on groups of animals with contrasting phenotypes, strongly impacting male or female fertility. Hundreds of thousands of matings between genotyped animals have made it possible to study the interactions of parental genomes on insemination outcomes, and to initiate studies on compatibility between animals. Finally, works on gestation length in 16 French breeds has added to our knowledge on the heritability and variability of this trait, and described the risks associated with selection for shorter gestations. All these results show that cattle can be used as a model for genetic research, thanks to the data routinely generated on the farm. They should also be used in genetic selection to improve animal fertility, a key factor in the sustainability of cattle farming
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Harvey, John Steven. "Metachromatic leukodystrophy : the role of non-pathogenic sequence variants in the causation of disease /". Title page, contents and abstract only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phh341.pdf.
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Boudellioua, Imene. "Semantic Prioritization of Novel Causative Genomic Variants in Mendelian and Oligogenic Diseases". Diss., 2019. http://hdl.handle.net/10754/631708.
Testo completoAbstract (sommario):
Recent advances in Next Generation Sequencing (NGS) technologies have facilitated the generation of massive amounts of genomic data which in turn is bringing the promise that personalized medicine will soon become widely available. As a result, there is an increasing pressure to develop computational tools to analyze and interpret genomic data. In this dissertation, we present a systematic approach for interrogating patients’ genomes to identify candidate causal genomic variants of Mendelian and oligogenic diseases. To achieve that, we leverage the use of biomedical data available from extensive biological experiments along with machine learning techniques to build predictive models that rival the currently adopted approaches in the field. We integrate a collection of features representing molecular information about the genomic variants and information derived from biological networks. Furthermore, we incorporate genotype-phenotype relations by exploiting semantic technologies and automated reasoning inferred throughout a cross-species phenotypic ontology network obtained from human, mouse, and zebra fish studies. In our first developed method, named PhenomeNet Variant Predictor (PVP), we perform an extensive evaluation of a large set of synthetic exomes and genomes of diverse Mendelian diseases and phenotypes. Moreover, we evaluate PVP on a set of real patients’ exomes suffering from congenital hypothyroidism. We show that PVP successfully outperforms state-of-the-art methods, and provides a promising tool for accurate variant prioritization for Mendelian diseases. Next, we update the PVP method using a deep neural network architecture as a backbone for learning and illustrate the enhanced performance of the new method,
DeepPVP on synthetic exomes and genomes. Furthermore, we propose OligoPVP, an extension of DeepPVP that prioritizes candidate oligogenic combinations in personal exomes and genomes by integrating knowledge from protein-protein interaction networks and we evaluate the performance of OligoPVP on synthetic genomes created by known disease-causing digenic combinations. Finally, we discuss some limitations and future steps for extending the applicability of our proposed methods to identify the genetic underpinning for Mendelian and oligogenic diseases.
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Chen, I.-Hsuan, e 陳怡璇. "Causative Variants and Related Passives in Southern Min: A Case Study of Grammaticalization". Thesis, 2009. http://ndltd.ncl.edu.tw/handle/26812038809635265208.
Testo completoAbstract (sommario):
碩士國立清華大學
語言學研究所
97
明清時代閩南語戲文富含使役與致使動詞，如：「chhoa7拽、kah4 甲、sai2 使、kio3 叫、khit4 乞和thoo3 度」。雖有類似的語法功能，且都出現於兼語式中，但每個動詞的語法化途徑不同，虛化程度不一，皆與其原本的語意緊密相關。藉由早期與現代閩南語的比較，可發現這些動詞的語意擴張將會影響兼語結構的解釋，主要歸納為兩條路線。其一為從動態使役到靜態致使，如「甲、叫」的語意泛化造成命令意涵減低，在特定的結構內主語可為非動物性的事件。「使」於早期閩南語為使役動詞，但現今與禁忌語衝突而不再沿用此功能。「拽」非使役動詞，但獨立發展出靜態致使用法。其二則為由雙賓動詞轉入被動用法，如給予動詞「乞、度」。「乞、度」在兼語結構已發展出容讓使役用法，若主語含有非出自意願允讓之意，易有容讓與被動的模糊解釋地帶，進而推衍出被動用法。本文進一步比較閩南語和官話致使動詞在語法化歷程上所反映的不同步現象，閩南語動態致使極少發展成成熟的靜態致使，但官話卻極為普遍。此外，官話的動態使役動詞可轉為被動用法，但閩南語的被動卻來自雙賓動詞。此六個使役與致使動詞皆作為兩個事件的連接點，因此當語意擴張時易造成兩個事件的關係重新詮釋，賦予兼語結構新的解讀。
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Chou, Yuh-Tsyr, e 周毓慈. "Identifying Causative Genetic Variants of Pheochromocytoma and Paraganglioma by Next-Generation Sequencing (NGS) in Taiwan". Thesis, 2019. http://ndltd.ncl.edu.tw/handle/3fhsqv.
Testo completoAbstract (sommario):
碩士國立臺灣大學
分子醫學研究所
107
Pheochromocytoma (PCC) and paraganglioma (PGL) are neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells respectively. They mostly present benign, yet show high morbidity and mortality due to the overproduction of catecholamine, which leads to hypertension, arrhythmia and even ischemia stroke. About one thirds of PCC/PGL are caused by germline genetic variants; therefore, here we established a NGS panel to detect possible disease-causing variants. After literature review, we aimed at the top 12 PCC/PGL causative genes (RET, VHL, NF1,FH, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, TMEM127, EGLN1(PHD2)), 10 somatic mutation genes (ARNT(HIF1β), ATRX, BRAF, CSDE1, EPAS1(HIF1α), FGFR1, HRAS, IDH1, SETD2, TP53), 3 fusion genes (BRAF, MAML3, NGFR) and other 7 genes (CDKN2A , H3F3A, IDH2, KMT2D, MDH2C, MERTK, MET) which were reported relative to PCC/PGL. Paired-end reads were generated from Illumina MiSeq platform and analyzed with in-house pipeline (BWA-MEM, Picard SortSam, MarkDuplicates, GATK-BQSR and ANNOVAR). Variants were filtering according to the allele frequencies in gnomAD, ExAC and Taiwan Biobank, and the pathogenicity interpretation were facilitated by disease/gene database, scientific literature and the 2015 ACMG Guidelines. In this study, we sequenced 41 probands and yielded approximately 29% diagnosis rate with identifying 7 different disease-causing variants and several variants of unknown significant (VUS). Among the results, seven unrelated probands carried a same causative variant in SDHD (c.3G>C, p.M1X, NM_003002), which implied a founder mutation in Taiwan. Three different variants of SDHB and SDHD in nine unrelated probands showed metastasis in our study. Variants in TMEM127 and RET showed low allele frequency or absent in population database and predicted to affect protein function deserved further functional study.
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Xavier, Alexandre. "Identification of new causative genes in inherited colorectal cancer". Thesis, 2020. http://hdl.handle.net/1959.13/1417893.
Testo completoAbstract (sommario):
Research Doctorate - Doctor of Philosophy (PhD)Colorectal cancer (CRC) remains a heavy burden for all national health systems. It is the third most frequently diagnosed cancer and the second leading cause of death in Australia and worldwide. Around 80% of CRC diagnosed each year are sporadic and somewhere between 7% and 8% have a clearly identified genetic predisposition (inherited CRC cancer; 5% for Lynch Syndrome (LS), 1% for Familial Adenomatous Polyposis (FAP) and 1-2% inclusive for various syndromes with very low incidences), with the remaining ~ 12%-13% being described as “familial”. For many patients with a clinical diagnosis of LS and FAP, no causative mutation has been identified in MSH6, MLH1, MSH2 or PMS2 (for LS patients) and in APC or MUTYH (for FAP patients) as a result of genetic testing. For those patients and their families, it is critical to identify the genetic cause underlying their increased CRC risk to offer early detection, tightened monitoring and, if required, suitable surgical management. Establishing an exhaustive list of known genetic risk factors for inherited CRC is essential for families burdened with a high incidence of CRC. Patients with a strong family history of CRC will usually undergo a tighten monitoring. Removing this psychological burden in individuals proven to be non-carriers of pathogenic germline variants is critical. Initial investigations focused on the Mismatch Repair (MMR) pathway in patients with LS and those with Lynch-Like Syndromes (LLS). 274 DNA samples from LLS patients were sequenced for the 22 genes involved in the MMR pathway to determine the presence of pathogenic variants. The results confirmed that LLS patients harbour pathogenic variants in genes that are not part of routine clinical screening: POLD1, EXO1, MLH3, RFC1 and RPA1. The results indicate that additional MMR genes are involved in the increased risk of CRC in LLS patients. As the technology evolved and became more cost-effective, whole exome sequencing (WES) was employed. Forty-eight patients with a clinical diagnosis of FAP were recruited based on their family history of CRC, their polyp status and their negative mutational status of APC and/or MUTYH. WES was used to interrogate all coding regions of the genome. Analysis of pathogenic variants showed that genes involved in DNA repair were frequently associated with a pathogenic variant. In addition, CNV analysis revealed the deletion of large portions of CFHR3, known to cause Atypical Haemolytic Uremic Syndrome, leading to ulcerative colitis, a known risk factor in CRC. Analysing the Polygenic Risk Score (PRS) for CRC risk-factors show an enrichment in inflammatory bowel syndrome-related markers. During the WES analysis of FAP-like patients, an absence of a precise and automated method to predict pathogenicity in cohorts sharing the same phenotype was apparent. To overcome this, we developed TAPES, a bioinformatics tool that can predict pathogenicity more precisely that can also calculate variant enrichment using only publicly available control sequences. TAPES also integrate powerful variant filtering and can generate useful reports (such as pathway analysis or calculating the total gene burden in a cohort). In conclusion, the research presented herein helps strengthen the knowledge of familial CRC. The involvement of novel MMR genes in LLS was also revealed thereby expanding the known number of genes associated with this disorder. DNA-repair related genes as well as those involved in inflammation were shown to play an important role in FPS. Finally, a refined analytical pipeline for WES sequencing interpretation was developed providing new bioinformatics tools for the rapid delivery of results.
Libri sul tema "Causative variants"
1
Hans, Steiner, Daniels Whitney, Kelly Michael e Stadler Christina. Etiology of Disruptive Behavior Disorders. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190265458.003.0004.
Testo completoAbstract (sommario):
This chapter discusses the growing data base examining the biological, psychological, and social factors causing disruptive behavior disorders (DBDs). Some of the most intriguing findings are derived from the clinical and preclinical studies of psychopathy, the most extreme and pathological variant of antisocial and aggressive behavior. The existing data are best accommodated in a risk/resilience model informed by developmental psychopathology, rather that a reductionist biological model. The most likely model of causation of DBDs will be multifactorial rather than unifactorial. It is also likely that different syndromes within the DBD grouping will be informed by very different admixtures of biological, psychological, and social factors, which in turn have important implications for effective treatments. The current descriptive diagnoses are inadequate for a sophisticated empirical understanding of DBDs.
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Anjum, Rani Lill, e Stephen Mumford. What’s in a Correlation? Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780198733669.003.0004.
Testo completoAbstract (sommario):
It might be thought that there is no longer any need to attack regularities theories of causation. But they remain influential insofar as they persist in the notion of correlation. Correlation can mean at least five different things: regularity, co-variance, stable proportion, invariance, and constancy. Discovery of correlation is often assumed as the proper starting point of causal science. Correlation between A and B can itself be due to many things, including pure coincidence. Bradford Hill suggested a more sophisticated approach to correlation that aimed to isolate the true causes. Statistical approaches now purport to do this better. All five types of correlation can be understood as worldly regularity so this is the concept that requires detailed scrutiny.
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Petchey, Owen L., Andrew P. Beckerman, Natalie Cooper e Dylan Z. Childs. Insights from Data with R. Oxford University Press, 2021. http://dx.doi.org/10.1093/oso/9780198849810.001.0001.
Testo completoAbstract (sommario):
Knowledge of how to get useful information from data is essential in the life and environmental sciences. This book provides learners with knowledge, experience, and confidence about how to efficiently and reliably discover useful information from data. The content is developed from first- and second-year undergraduate-level courses taught by the authors. It charts the journey from question, to raw data, to clean and tidy data, to visualizations that provide insights. This journey is presented as a repeatable workflow fit for use with many types of question, study, and data. Readers discover how to use R and RStudio, and learn key concepts for drawing appropriate conclusions from patterns in data. The book focuses on providing learners with a solid foundation of skills for working with data, and for getting useful information from data summaries and visualizations. It focuses on the strength of patterns (i.e. effect sizes) and their meaning (e.g. correlation or causation). It purposefully stays away from statistical tests and p-values. Concepts covered include distribution, sample, population, mean, median, mode, variance, standard deviation, correlation, interactions, and non-independence. The journey from data to insight is illustrated by one workflow demonstration in the book, and three online. Each involves data collected in a real study. Readers can follow along by downloading the data, and learning from the descriptions of each step in the journey from the raw data to visualizations that show the answers to the questions posed in the original studies.
Capitoli di libri sul tema "Causative variants"
1
Muise, Aleixo, e Hailiang Huang. "Sequencing and Mapping IBD Genes to Individual Causative Variants and Their Clinical Relevance". In Molecular Genetics of Inflammatory Bowel Disease, 117–39. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-28703-0_6.
Testo completo
2
Khimsuriya, Yashvant, Salil Vaniyawala, Babajan Banaganapalli, Muhammadh Khan, Ramu Elango e Noor Ahmad Shaik. "Finding a Needle in a Haystack: Variant Effect Predictor (VEP) Prioritizes Disease Causative Variants from Millions of Neutral Ones". In Essentials of Bioinformatics, Volume II, 85–104. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-18375-2_6.
Testo completo
3
Krickel, Beate. "Different Types of Mechanistic Explanation and Their Ontological Implications". In History, Philosophy and Theory of the Life Sciences, 9–28. Cham: Springer International Publishing, 2023. http://dx.doi.org/10.1007/978-3-031-46917-6_2.
Testo completoAbstract (sommario):
AbstractOne assumption of the new mechanistic approach is that there are two kinds of mechanistic explanations: etiological and constitutive ones. While the former explain phenomena in terms of their preceding causes, the latter are supposed to refer to mechanisms that constitute phenomena. Based on arguments by Kaiser and Krickel (Br J Philos Sci 68(3):745–779, 2017) and Krickel (The mechanical world, vol. 13, Springer International Publishing. https://doi.org/10.1007/978-3-030-03629-4, 2018), I will show that this view is too narrow. Indeed, three different types of explanation are usually subsumed under the label “constitutive explanation”. However, one of those types of explanation is not a version of constitutive explanation. Rather it is a variant of etiological explanation. As a result, I will show that there are four types of mechanistic explanation, two variants of etiological explanation—which I will call output mechanistic explanations and input-output mechanistic explanations—and two variants of constitutive explanation—which I will call filler mechanistic explanations and dimensioned mechanistic explanations. Keeping these apart is crucial as they come with different ontological implications. An evaluation of the mechanistic approach regarding its stance on reduction, levels, and interlevel causation crucially depends on which notion of mechanistic explanation one has in mind.
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Pereira, Sandra, Mariana Adrião, Mafalda Sampaio, Margarida Ayres Basto, Esmeralda Rodrigues, Laura Vilarinho, Elisa Leão Teles, Isabel Alonso e Miguel Leão. "Mitochondrial Encephalopathy: First Portuguese Report of a VARS2 Causative Variant". In JIMD Reports, 113–19. Berlin, Heidelberg: Springer Berlin Heidelberg, 2018. http://dx.doi.org/10.1007/8904_2018_89.
Testo completo
5
Noor Ul Ayan, Hafiza, e Muhammad Tariq. "Genome-Wide Association Studies (GWAS)". In Omics Technologies for Clinical Diagnosis and Gene Therapy: Medical Applications in Human Genetics, 60–78. BENTHAM SCIENCE PUBLISHERS, 2022. http://dx.doi.org/10.2174/9789815079517122010008.
Testo completoAbstract (sommario):
Genome-wide association studies (GWAS) are designed to find associations between genomic variants and a phenotype, usually a complex multifactorial disease. The idea for association studies in a large cohort was floated after linkage analysis, which proved extremely successful in the identification of causative genes for rare disorders, but it did not come up to expectations in the case of common complex disorders where causative alleles are less frequently aggregated in families. Ever since their advent in 2005, GWAS have transformed gene identification ventures in complex disease genetics over the past fifteen years, giving rise to several powerful associations for complex traits and disorders. Association studies are based on the “common disease common variant” hypothesis which assumes that genomic variation with low penetrance and high population frequency are involved in the causation of common complex disorders. Although GWAS, complemented with the downstream functional assessment of the variants, have been successful in identifying novel disease-causing genes and biological mechanisms, the field has also received intense criticism over the years, especially its failure in tracing the so-called ‘missing heritability’. Therefore, further functional studies are mandatory to precisely establish a link between risk alleles and a phenotype. This chapter broadly covers an introduction of GWAS, their successes and limitations, and various important factors affecting the design and results, followed by challenges in the post-GWAS era.
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Snyder, Michael. "Complex Genetic Diseases". In Genomics and Personalized Medicine. Oxford University Press, 2016. http://dx.doi.org/10.1093/wentk/9780190234775.003.0006.
Testo completoAbstract (sommario):
What is a complex genetic disease? Although great strides have been made to identify single gene variants that have a strong causative effect for a particular disease (e.g., CFTR mutations for cystic fibrosis and HEXA mutations for Tay-Sachs disease), the...
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Mefford, Heather C. "Rare Variants of Substantial Effect in Psychiatric Disorders of Childhood Onset". In Neurobiology of Mental Illness, a cura di Joseph D. Buxbaum, 944–54. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199934959.003.0071.
Testo completoAbstract (sommario):
Psychiatric disorders in children, including autism, intellectual disability, attention deficit hyperactivity disorder, childhood-onset schizophrenia and bipolar disorder carry a significant financial and social burden for affected individuals and their families. It is clear that genetic factors play an important role in the etiology of many psychiatric illnesses. However, the inheritance pattern of each of these disorders is not straightforward, and therefore the identification of specific causative genes has been difficult. Recent technological advances facilitate genome-wide studies to identify both common and rare genetic variants in large numbers of individuals. In this chapter, we will review evidence that suggests that rare genetic variants, including both single nucleotide and copy number variants, contribute to the genetic risk of childhood-onset psychiatric disease.
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Arnar, David O., e Hilma Holm. "Mechanisms of atrial fibrillation: genetics". In ESC CardioMed, 2120–25. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0497.
Testo completoAbstract (sommario):
While atrial fibrillation (AF) is common and has serious consequences, a lot is yet unknown about the causative factors underlying this arrhythmia. The role of genetics in the development of AF has become more evident in the past decade. Family history is now a firmly established risk factor and many common and rare sequence variants linked to AF have been identified. Genome-wide association studies have identified common sequence variants that associate with AF, including variants on chromosomes 4q25, 16q22, and 1q22. Nevertheless, it has become apparent that despite these findings, a substantial fraction of heritability of most complex traits remained unaccounted for. This raises the possibility that development of AF is determined by the combination of common and rare susceptibility variants. Whole genome sequencing is the most comprehensive method to analyse individual genetic variation. A paradigm shift from microarray-based genotyping studies to whole exome and whole genome sequencing is ongoing. Whole genome sequencing studies have shown mutations in myosin genes may be associated with AF, implying that variants encoding sarcomere genes may be involved in the development of this arrhythmia. While some of the sequence variants discovered suggest novel mechanisms in the pathophysiology of this complex arrhythmia, much work is still needed to fully understand the mechanisms linking many of these loci to AF. Likewise, the current clinical applicability of this information is still unclear. However, further developments in this field are expected to add to our understanding of this complex arrhythmia and hopefully lead to new therapeutic possibilities.
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Acharya, Anu, Shibichakravarthy Kannan, Brajendra Kumar, Jasmine Khurana, Sushma Patil e Geethanjali Tanikella. "Impact of Human Exome Sequencing on Clinical Research". In Healthcare Ethics and Training, 603–24. IGI Global, 2017. http://dx.doi.org/10.4018/978-1-5225-2237-9.ch027.
Testo completoAbstract (sommario):
Recent advances in human exome sequencing and the associated advantages have made it a technology of choice in various domains. The savings in time, cost and data storage compared with whole genome sequencing make this technology a potential game changer in clinical research settings. Recent advances in NGS have made it feasible to use exome sequencing in clinical research for identifying novel and rare variants that can lead to change in protein structure and function which may finally culminate into a totally different phenotype. If whole exome is not desired the same technology can be used for studying target exonic regions to investigate causative genes for a specific phenotype associated with disease. Exome sequencing has emerged as an effective and efficient tool for the translational and clinical research. There is a demand for systematically storing variant information in large databanks. Meaningful information from the exome-seq data can be combined with other data. This can be correlated with clinical findings within a clinical trial setting for a better study outcome.
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Pilichou, Kalliopi, Cristina Basso, Rudy Celeghin e Gaetano Thiene. "Genetics of cardiomyopathies: arrhythmogenic right ventricular cardiomyopathy". In ESC CardioMed, 699–705. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0157.
Testo completoAbstract (sommario):
Arrhythmogenic cardiomyopathy (AC) is characterized by progressive non-ischaemic cardiomyocyte death and fibro-fatty repair, triggering ventricular arrhythmias and sudden death. A familial background consistent with an autosomal dominant trait of inheritance is described in nearly half of AC patients, even if recessive variants have also been reported, either associated or not with palmoplantar keratosis and woolly hair. Advances in DNA sequencing have led to the identification of more than 350 pathogenic mutations in 15 disease-causing genes associated with AC. Nearly half of patients with AC harbour mutations in genes encoding desmosomal proteins (plakoglobin, JUP; desmoplakin, DSP; plakophillin-2, PKP2; desmoglein-2, DSG2; and desmocollin-2, DSC2) and less than 1% carry mutations in non-desmosomal genes (transforming growth factor beta-3, TGFB3; desmin, DES; alpha-T catenin, CTNNA3; phospholamban, PLN; lamin A/C, LMNA; titin, and TTN; ryanodine receptor-2, RYR2). The inheritance pattern of AC is more complex than previously appreciated, with frequent requirement of more than one mutation for fully penetrant disease. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, explaining in part the phenotypic variability. In the era of next-generation sequencing, parallel analysis of thousands of genes is feasible and many rare variants can be detected (nearly 1000 nucleotide variants of unknown significance have been linked to AC), so the challenge is to distinguish causative mutations from the genetic noise since genetic testing may be a precious tool in distinguishing AC patients at risk of disease onset and of sudden death.
Atti di convegni sul tema "Causative variants"
1
Coggins, Nicole, Luis Carvajal-Carmona e David Segal. "Abstract 1117: Who's in the driver's seat? Identifying causative variants of colorectal cancer". In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-1117.
Testo completo
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Santana, B. F., M. Riser e B. Fragomeni. "297. Alternative SNP weighting for genomic prediction methods in the presence of causative variants". In World Congress on Genetics Applied to Livestock Production. The Netherlands: Wageningen Academic Publishers, 2022. http://dx.doi.org/10.3920/978-90-8686-940-4_297.
Testo completo
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Yuan, C., L. Tang, T. Lopdell, C. Oget-Ebrad, G. Costa Monteiro Moreira, J. L. Gualdron, Z. Cheng et al. "497. Enrichment of causative variants in tissue-specific and shared ATAC-Seq peaks in cattle". In World Congress on Genetics Applied to Livestock Production. The Netherlands: Wageningen Academic Publishers, 2022. http://dx.doi.org/10.3920/978-90-8686-940-4_497.
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Samoilova, Anna. "Effect of phages isolated from different sources against fire blight pathogen". In 5th International Scientific Conference on Microbial Biotechnology. Institute of Microbiology and Biotechnology, Republic of Moldova, 2022. http://dx.doi.org/10.52757/imb22.29.
Testo completoAbstract (sommario):
Fire blight of rosaceous plants is one of the economically most important diseases of fruit trees caused by the bacterium Erwinia amylovora. Plants are extremely vulnerable for fire blight infection at the bloom stage. Blossom blight can lead to the great crop losses and even the plant death. Since chemical treatments are forbidden in time of blossoming, bacteriophages, highly specific bacterial viruses could be used for the disease control. Being the natural components of ecosystems, phages infect only bacteria sensitive to them, are non-toxic to plants, animals and humans and are adapted to the bacteria environment. It has been shown that bacterium E. amylovora expresses its major pathogenicity factors during immature pear tissues infection. Therefore, in this study, the ability of four virulent E. amylovora bacteriophages, isolated from the aerial parts of the affected plants (phage isolate 1 from quince tissues; phage isolate 2 from hawthorn, Republic of Moldova) and from natural water reservoirs near fruits orchards or wild rosaceous trees (phage isolates 3 and 4, Swiss Confederation) to inhibit E. amylovora growth in the immature pear tissues was evaluated. Immature pear slices were inoculated with suspensions of E. amylovora CFBP1430 and EaM contained 104 CFU/ml. After four hours incubation in the humidified chamber at 280C infected immature pear slices were treated with 107 PFU/ml of phage isolates. Pear slices, treated with sterile distilled water were used as a control. Symptoms were recorded at 1, 2, 3, 5, 6, 7 and 8 days after inoculation. For each bacteria strain/phage isolate combination tested pear slices were assayed in triplicate and each experiment was repeated at least two times. Immature pear slices infected with bacteria EaM displayed the first symptoms of the fire blight, ooze formation and light necrosis, one day after inoculation. Pear slices, infected with E. amylovora CFBP1430 demonstrated ooze and necrosis two days after inoculation. In the bacteria/phage combinations the first symptoms of the fire blight appeared on the sixth day after inoculation in the variants of EaM/phage isolate 3 and CFBP1430/phage isolate 3. On the seventh and eighth days after inoculation symptoms of the fire blight infection have been recorded in the EaM/phage isolate 2 and CFBP1430/ phage isolate 2, respectively. Bacteria/phage combinations EaM/phage isolate 4 and CFBP1430/ phage isolate 4 showed disease symptoms on the seventh day after inoculation. Immature pear slices in the variants EaM/phage isolate 1 and CFBP1430/phage isolate 1 showed necrotic lesion eight days after inoculation. Thus, phage isolate 4, detected in water was able to suppress growth of phytopathogenic E. amylovora just a day less than highly virulent phage isolate 1 detected in the quince tissues. The conducted experiments have demonstrated that bacteriophages isolated from water revealed high efficacy against bacteria E. amylovora and all studied phage isolates successfully inhibited the fire blight causative agent growth in the plant host tissues for about seven days. Hence it has been shown that treatment with bacteriophages for the fire blight control in the fruit orchard should be carried out weekly if environmental conditions are favorable for the disease development.
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Zhang, Yi, Mohith Manjunath, Shilu Zhang, Deborah Chasman, Sushmita Roy e Jun S. Song. "Abstract 1220: Integrative genomic analysis discovers the causative regulatory mechanisms of a breast cancer-associated genetic variant". In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1220.
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Horváth, Imre, Yongzhe Li, Zoltán Rusák, Wilhelm Frederik Van Der Vegte e Guangjun Zhang. "Dynamic Spatial Context Computation for Time-Varying Process Scenarios". In ASME 2016 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. American Society of Mechanical Engineers, 2016. http://dx.doi.org/10.1115/detc2016-59046.
Testo completoAbstract (sommario):
There are many real life processes whose smart control requires processing context information. Though the issue of processing varying context information has been addressed in the literature, domain independent solutions that can support reasoning and decision making according to time-varying process scenarios in multiple application fields are scarce. This paper proposes a method for dynamic context computation concerning spatial and attributive information. Context is interpreted as a body of information dynamically created by a pattern of entities and relationships over a history of situations. Time is conceived as a causative force capable of changing situations, and acting on people and objects. The invariant and variant spatial information is captured by a two-dimensional spatial feature representation matrix. The time-dependent changes in the context information are computed based on a dynamic context information management hyper-matrix. This humble but powerful representation lends itself to a quasi-real time computing and is able to provide information about foreseeable happenings over multiple situations. The paper uses the practical case of evacuation of a building in fire both as an explorative case for conceptualization of the functionality of the computational mechanism and as a demonstrative and testing application. Our intention is to use the dynamic context computation mechanism as a kernel component of a reasoning platform for informing cyber physical systems.
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Kim, Jaehyun, e David Wallace. "A Statistical Approach to Causality Analysis in a Distributed Design Framework". In ASME 2004 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2004. http://dx.doi.org/10.1115/detc2004-57694.
Testo completoAbstract (sommario):
Numerous collaborative design tools have been developed to accelerate the product development, and recently environments for building distributed simulations have been proposed. For example, a simulation framework called DOME (Distributed Object-oriented Modeling and Evaluation) has been developed in MIT CADLAB. DOME is unique in its decentralized structure that allows heterogeneous simulations to be stitched together while allowing proprietary information an simulation models to remain secure with each participant. While such an approach offers many advantages, it also hides causality and sensitivity information, making it difficult for designers to understand problem structure and verify solutions. The purpose of this research is to analyze the relationships between design parameters (causality) and the strength of the relationships (sensitivity) in decentralized web-based design simulation. Algorithms and implementations for the causality and sensitivity analysis are introduced. Causality is determined using Granger’s definition of causality, which is to distinguish causation from association using conditional variance of the suspected output variable. Sensitivity is estimated by linear regression analysis and a perturbation method, which transfers the problem into a frequency domain by generating periodic perturbations. Varying Internet latency and disturbances are problematic issues with these methods. Thus, new algorithms are developed and tested to overcome these problems.
Rapporti di organizzazioni sul tema "Causative variants"
1
Weller, Joel I., Derek M. Bickhart, Micha Ron, Eyal Seroussi, George Liu e George R. Wiggans. Determination of actual polymorphisms responsible for economic trait variation in dairy cattle. United States Department of Agriculture, gennaio 2015. http://dx.doi.org/10.32747/2015.7600017.bard.
Testo completoAbstract (sommario):
The project’s general objectives were to determine specific polymorphisms at the DNA level responsible for observed quantitative trait loci (QTLs) and to estimate their effects, frequencies, and selection potential in the Holstein dairy cattle breed. The specific objectives were to (1) localize the causative polymorphisms to small chromosomal segments based on analysis of 52 U.S. Holstein bulls each with at least 100 sons with high-reliability genetic evaluations using the a posteriori granddaughter design; (2) sequence the complete genomes of at least 40 of those bulls to 20 coverage; (3) determine causative polymorphisms based on concordance between the bulls’ genotypes for specific polymorphisms and their status for a QTL; (4) validate putative quantitative trait variants by genotyping a sample of Israeli Holstein cows; and (5) perform gene expression analysis using statistical methodologies, including determination of signatures of selection, based on somatic cells of cows that are homozygous for contrasting quantitative trait variants; and (6) analyze genes with putative quantitative trait variants using data mining techniques. Current methods for genomic evaluation are based on population-wide linkage disequilibrium between markers and actual alleles that affect traits of interest. Those methods have approximately doubled the rate of genetic gain for most traits in the U.S. Holstein population. With determination of causative polymorphisms, increasing the accuracy of genomic evaluations should be possible by including those genotypes as fixed effects in the analysis models. Determination of causative polymorphisms should also yield useful information on gene function and genetic architecture of complex traits. Concordance between QTL genotype as determined by the a posteriori granddaughter design and marker genotype was determined for 30 trait-by-chromosomal segment effects that are segregating in the U.S. Holstein population; a probability of <10²⁰ was used to accept the null hypothesis that no segregating gene within the chromosomal segment was affecting the trait. Genotypes for 83 grandsires and 17,217 sons were determined by either complete sequence or imputation for 3,148,506 polymorphisms across the entire genome. Variant sites were identified from previous studies (such as the 1000 Bull Genomes Project) and from DNA sequencing of bulls unique to this project, which is one of the largest marker variant surveys conducted for the Holstein breed of cattle. Effects for stature on chromosome 11, daughter pregnancy rate on chromosome 18, and protein percentage on chromosome 20 met 3 criteria: (1) complete or nearly complete concordance, (2) nominal significance of the polymorphism effect after correction for all other polymorphisms, and (3) marker coefficient of determination >40% of total multiple-regression coefficient of determination for the 30 polymorphisms with highest concordance. The missense polymorphism Phe279Tyr in GHR at 31,909,478 base pairs on chromosome 20 was confirmed as the causative mutation for fat and protein concentration. For effect on fat percentage, 12 additional missensepolymorphisms on chromosome 14 were found that had nearly complete concordance with the suggested causative polymorphism (missense mutation Ala232Glu in DGAT1). The markers used in routine U.S. genomic evaluations were increased from 60,000 to 80,000 by adding markers for known QTLs and markers detected in BARD and other research projects. Objectives 1 and 2 were completely accomplished, and objective 3 was partially accomplished. Because no new clear-cut causative polymorphisms were discovered, objectives 4 through 6 were not completed.
2
Gelb, Jr., Jack, Yoram Weisman, Brian Ladman e Rosie Meir. Identification of Avian Infectious Brochitis Virus Variant Serotypes and Subtypes by PCR Product Cycle Sequencing for the Rational Selection of Effective Vaccines. United States Department of Agriculture, dicembre 2003. http://dx.doi.org/10.32747/2003.7586470.bard.
Testo completoAbstract (sommario):
Objectives 1. Determine the serotypic identities of 40 recent IBV isolates from commercial chickens raised in the USA and Israel. 2. Sequence all IBV field isolates using PCR product cycle sequencing and analyze their S 1 sequence to detennine their homology to other strains in the Genbank and EMBL databases. 3. Select vaccinal strains with the highest S 1 sequence homology to the field isolates and perform challenge of immunity studies in chickens in laboratory trials to detennine level of protection afforded by the vaccines. Background Infectious bronchitis (IB) is a common, economically important disease of the chicken. IB occurs as a respiratory form, associated with airsacculitis, condemnation, and mortality of meat-type broilers, a reproductive form responsible for egg production losses in layers and breeders, and a renal form causing high mortality in broilers and pullets. The causative agent is avian coronavirus infectious bronchitis virus (IBV). Replication of the virus' RNA genome is error-prone and mutations commonly result. A major target for mutation is the gene encoding the spike (S) envelope protein used by the virus to attach and infect the host cell. Mutations in the S gene result in antigenic changes that can lead to the emergence of variant serotypes. The S gene is able to tolerate numerous mutations without compromising the virus' ability to replicate and cause disease. An end result of the virus' "flexibility" is that many strains of IBV are capable of existing in nature. Once formed, new mutant strains, often referred to as variants, are soon subjected to immunological selection so that only the most antigenically novel variants survive in poultry populations. Many novel antigenic variant serotypes and genotypes have been isolated from commercial poultry flocks. Identification of the field isolates of IBV responsible for outbreaks is critical for selecting the appropriate strain(s) for vaccination. Reverse transcriptase polymerase chain reaction (RT-PCR) of the Sl subunit of the envelope spike glycoprotein gene has been a common method used to identify field strains, replacing other time-consuming or less precise tests. Two PCR approaches have been used for identification, restriction fragment length polymorphism (RFLP) and direct automated cycle sequence analysis of a diagnostically relevant hypervariab1e region were compared in our BARD research. Vaccination for IB, although practiced routinely in commercial flocks, is often not protective. Field isolates responsible for outbreaks may be unrelated to the strain(s) used in the vaccination program. However, vaccines may provide varying degrees of cross- protection vs. unrelated field strains so vaccination studies should be performed. Conclusions RFLP and S1 sequence analysis methods were successfully performed using the field isolates from the USA and Israel. Importantly, the S1 sequence analysis method enabled a direct comparison of the genotypes of the field strains by aligning them to sequences in public databases e.g. GenBank. Novel S1 gene sequences were identified in both USA and Israel IBVs but greater diversity was observed in the field isolates from the USA. One novel genotype, characterized in this project, Israel/720/99, is currently being considered for development as an inactivated vaccine. Vaccination with IBV strains in the US (Massachusetts, Arkansas, Delaware 072) or in Israel (Massachusetts, Holland strain) provided higher degrees of cross-protection vs. homologous than heterologous strain challenge. In many cases however, vaccination with two strains (only studies with US strains) produced reasonable cross-protection against heterologous field isolate challenge. Implications S1 sequence analysis provides numerical similarity values and phylogenetic information that can be useful, although by no means conclusive, in developing vaccine control strategies. Identification of many novel S1 genotypes of IBV in the USA is evidence that commercial flocks will be challenged today and in the future with strains unrelated to vaccines. In Israel, monitoring flocks for novel IBV field isolates should continue given the identification of Israel/720/99, and perhaps others in the future. Strains selected for vaccination of commercial flocks should induce cross- protection against unrelated genotypes. Using diverse genotypes for vaccination may result in immunity against unrelated field strains.