Academic literature on the topic 'Non coding variations'
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Journal articles on the topic "Non coding variations"
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Pan, Qi, Yue-Juan Liu, Xue-Feng Bai, Xiao-Le Han, Yong Jiang, Bo Ai, Shan-Shan Shi, et al. "VARAdb: a comprehensive variation annotation database for human." Nucleic Acids Research 49, no. D1 (October 23, 2020): D1431—D1444. http://dx.doi.org/10.1093/nar/gkaa922.
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Abstract With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include ‘Variation information’, ‘Regulatory information’, ‘Related genes’, ‘Chromatin accessibility’ and ‘Chromatin interaction’. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes.
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Laurent, Jon M., Sudarshan Pinglay, Leslie Mitchell, and Ran Brosh. "Probing the dark matter of the human genome with big DNA." Biochemist 41, no. 3 (June 1, 2019): 46–48. http://dx.doi.org/10.1042/bio04103046.
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Less than 2% of our genome is protein-coding DNA. The vast expanses of non-coding DNA make up the genome's “dark matter”, where introns, repetitive and regulatory elements reside. Variation between individuals in non-coding regulatory DNA is emerging as a major factor in the genetics of numerous diseases and traits, yet very little is known about how such variations contribute to disease risk. Studying the genetics of regulatory variation is technically challenging as regulatory elements can affect genes located tens of thousands of base pairs away, and often, multiple distal regulatory variations, each with a very small effect, combine in an unknown way to significantly modulate the expression of genes. At the Center for Synthetic Regulatory Genomics (SyRGe) we directly tackle these problems in order to systematically elucidate the mechanisms of regulatory variation underlying human disease.
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Sedláková, V., P. Sedlák, D. Zeka, J. Domkářová, P. Doležal, and P. Vejl. "Evaluation of variations in plastid DNA non-coding regions in selected species of the genus Solanum." Czech Journal of Genetics and Plant Breeding 53, No. 3 (September 13, 2017): 127–31. http://dx.doi.org/10.17221/76/2015-cjgpb.
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The diversity of three non-coding plastid DNA loci (trnL/trnF spacer, trnV/16SrRNA spacer, trnL/trnL intron) was assessed in 16 Solanum L. species (135 individuals). Polymorphisms were detected by denaturing gradient gel electrophoresis (DGGE) and verified by direct sequencing. No intraspecific diversity and only poor interspecific diversity was detected. Unique S. mochiquense Ochoa specific length polymorphism at the trnL/trnL locus represented by duplication of an 18 bp segment was discovered. The detected DGGE interspecific trnL/trnF locus polymorphism did not specifically associate with single point mutations in the sequence confirmed by sequencing. The DGGE method was found to be a simple and cheap pre-exploring tool for mutation detection in compared DNA regions. Some identified polymorphisms can be used in the management of genetic resources.
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Meerschaut, Ilse, Sarah Vergult, Annelies Dheedene, Björn Menten, Katya De Groote, Hans De Wilde, Laura Muiño Mosquera, et al. "A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome." Genes 12, no. 7 (July 8, 2021): 1048. http://dx.doi.org/10.3390/genes12071048.
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Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.
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Bhartiya, Deeksha, and Vinod Scaria. "Genomic variations in non-coding RNAs: Structure, function and regulation." Genomics 107, no. 2-3 (March 2016): 59–68. http://dx.doi.org/10.1016/j.ygeno.2016.01.005.
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Bozgeyik, Esra, and Ibrahim Bozgeyik. "Non-coding RNA variations in oral cancers: A comprehensive review." Gene 851 (January 2023): 147012. http://dx.doi.org/10.1016/j.gene.2022.147012.
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Scarpa, Aldo, and Andrea Mafficini. "Non-coding regulatory variations: the dark matter of pancreatic cancer genomics." Gut 67, no. 3 (June 28, 2017): 399–400. http://dx.doi.org/10.1136/gutjnl-2017-314310.
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Haas, Jan, Stefan Mester, Alan Lai, Karen S. Frese, Farbod Sedaghat‐Hamedani, Elham Kayvanpour, Tobias Rausch, et al. "Genomic structural variations lead to dysregulation of important coding and non‐coding RNA species in dilated cardiomyopathy." EMBO Molecular Medicine 10, no. 1 (November 14, 2017): 107–20. http://dx.doi.org/10.15252/emmm.201707838.
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Sedano, Melina J., Alana L. Harrison, Mina Zilaie, Chandrima Das, Ramesh Choudhari, Enrique Ramos, and Shrikanth S. Gadad. "Emerging Roles of Estrogen-Regulated Enhancer and Long Non-Coding RNAs." International Journal of Molecular Sciences 21, no. 10 (May 25, 2020): 3711. http://dx.doi.org/10.3390/ijms21103711.
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Genome-wide RNA sequencing has shown that only a small fraction of the human genome is transcribed into protein-coding mRNAs. While once thought to be “junk” DNA, recent findings indicate that the rest of the genome encodes many types of non-coding RNA molecules with a myriad of functions still being determined. Among the non-coding RNAs, long non-coding RNAs (lncRNA) and enhancer RNAs (eRNA) are found to be most copious. While their exact biological functions and mechanisms of action are currently unknown, technologies such as next-generation RNA sequencing (RNA-seq) and global nuclear run-on sequencing (GRO-seq) have begun deciphering their expression patterns and biological significance. In addition to their identification, it has been shown that the expression of long non-coding RNAs and enhancer RNAs can vary due to spatial, temporal, developmental, or hormonal variations. In this review, we explore newly reported information on estrogen-regulated eRNAs and lncRNAs and their associated biological functions to help outline their markedly prominent roles in estrogen-dependent signaling.
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Mattick, John S. "The central role of RNA in the genetic programming of complex organisms." Anais da Academia Brasileira de Ciências 82, no. 4 (December 2010): 933–39. http://dx.doi.org/10.1590/s0001-37652010000400016.
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Notwithstanding lineage-specific variations, the number and type of protein-coding genes remain relatively static across the animal kingdom. By contrast there has been a massive expansion in the extent of genomic non-proteincoding sequences with increasing developmental complexity. These non-coding sequences are, in fact, transcribed in a regulated manner to produce large numbers of large and small non-protein-coding RNAs that control gene expression at many levels including chromatin architecture, post-transcriptional processing and translation. Moreover, many RNAs are edited, especially in the nervous system, which may be the basis of epigenome-environment interactions and the function of the brain.
Dissertations / Theses on the topic "Non coding variations"
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González, Rosado Santiago. "Identification and characterization of non-coding genomic variations associated to cancer diseases." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/397789.
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The genetic and molecular bases of most of the human diseases have become one of the main goals of the human biology in the last decades. To be able to unveil the genetic variations and the affected cellular processes associated with a specific disease is crucial in order to generate accurate diagnosis and further therapies. The Next Generation Sequencing (NGS) revolution, with the associated reduction in time and costs of sequencing, has allowed the scientist to access large number of human genomes to their biomedical studies. The study of genetic disorders, cancer in particular, has benefit from NGS identifying genetic variations associated with a given disorder. All these new results, some of them in regions with unknown function, have generated a double challenge in the scientific community. Firstly, detect as much as possible all the different variants associated with a disease, in some complex diseases several. Secondly, to understand the functional impact those modifications are causing in the cell.
Regarding the first challenge, this thesis contributes in the identification of genetic modifications throw the development of a bioinformatics tool named SMUFIN (Moncunill et al. 2014). SMUFIN can detect somatic variants related with tumour development and progression in a quickly and effective way. Not limited to the software development, several tumours has been analysed and their somatic variants characterized. These tumours include mantel cell lymphoma, paediatric medulloblastoma and chronic lymphocytic leukaemia (Moncunill et al. 2014; Puente et al. 2015).
In the evaluation of the functional impact, the thesis also includes a method, RELA, to determine when these annotated variants play a regulatory role as enhancers or promoters (Gonzalez et al. 2012). Combined with other available data and a spread methodology to unveil regulatory regions evaluation of variants affecting regulatory regions have been performed in chronic lymphocytic leukaemia (details included in the thesis discussion).
To sum up, this thesis cover with methodology and provide bioinformatics tools to perform a complete genomic analysis of genetic variants in biomedicine studies. It includes from the identification of variants for each of the patients to the evaluation of their functional impact in the disease development and progression. This kind of approach is currently common in the research laboratories and it will be part of the healthcare system in a close future to diagnose and classify patients.El estudio de las bases genéticas y moleculares de las patologías humanas ha constituido el centro de atención de gran parte de la investigación en biología durante las últimas décadas con el fin último de comprender los procesos celulares alterados en cada caso y la posibilidad de generar protocolos de diagnosis y terapias específicas. Con la llegada de la denominada Next Generation Sequencing (NGS) y su consiguiente reducción en tiempo y costes ha permitido el acceso a la secuenciación de numeroso genomas humanos en el entorno biomédico. El estudio de enfermedades genéticas, y del cáncer en particular, se ha visto enormemente favorecido al poder incorporar un importante número de genomas de pacientes a sus estudios y así poder identificar directamente las mutaciones asociadas a cada patología. A su vez, esta revolución junto con la capacidad de detectar modificaciones genéticas en regiones cuya función todavía se desconoce, ha generado un doble desafío en la comunidad científica: por un lado el análisis de variantes genéticas asociadas a cada tipo de enfermedad y, por el otro, el entender el impacto funcional que dichas modificaciones provocan en la célula. Esta tesis contribuye a solucionar estas limitaciones a través del desarrollo de una aplicación, SMUFIN (Moncunill et al. 2014), que permite de forma rápida y eficaz la identificación de variaciones somáticas asociadas al desarrollo o progresión de tumores. También se describen los resultados obtenidos relativos a la identificación y caracterización de las reorganizaciones cromosómicas en cáncer, así como los resultados obtenido en cuanto a sus mecanismos e impacto funcional (Puente et al. 2015). Además, como parte de la anotación genómica para la interpretación funcional de las variaciones detectadas, esta tesis incluye los resultados del desarrollo de estrategias y metodologías para la detección de regiones reguladoras en genomas de eucariotas (Gonzalez et al. 2012). En resumen esta tesis intenta cubrir y dotar de herramientas bionformáticas para completar los pasos necesarios para el análisis de genomas en biomedicina, desde que un grupo de pacientes son secuenciados hasta que sus diferentes variantes son identificadas y su impacto funcional determinado. Este tipo de análisis, que ahora esta ocurriendo en el campo de la investigación, pronto será una realidad y una rutina en el sistema sanitario.
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Masson, Aymeric. "Approches multi-omiques des anomalies transcriptionnelles dans les maladies rares du développement." Electronic Thesis or Diss., Bourgogne Franche-Comté, 2024. http://www.theses.fr/2024UBFCI006.
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L’expression des gènes passe par le processus de transcription dans le noyau des cellules eucaryotes qui produit les ARNs, intermédiaires indispensables pour former des protéines. La synthèse et le devenir des ARNs sont soumis à un contrôle complexe assuré par de nombreux acteurs incluant entre autres les séquences d'ADN non codantes régulatrices qui assurent une régulation spatio-temporelle fine de l’expression génique et les ribonucléoprotéines hétérogènes nucléaires (hnRNP) capables de lier les molécules d’ARN et de réguler leur maturation, leur stabilité et leur localisation.L'approche standard actuelle pour l'exploration moléculaire des patients atteints d'anomalies du développement (AD) et/ou de déficience intellectuelle (DI), déploie la combinaison de l’analyse chromosomique par puces à ADN, le test de l’X fragile, le séquençage d'exome, et plus récemment le séquençage du génome pour établir un diagnostic moléculaire. L’ensemble de ces approches comporte un rendement diagnostique inférieur à 50% pour les AD/DI. Cependant, les analyses peuvent parfois mettre en évidence la présence de variations de signification incertaine dans des gènes candidats, non encore impliqués en pathologie humaine. Des tests fonctionnels sont alors nécessaires afin d’établir une correcte corrélation génotype-phénotype. De cette manière, des variations pathogènes ont été identifiées au sein de deux gènes candidats codant des hnRNPs intervenant dans le métabolisme des ARNs : PTBP1 et PTBP2. Le but de cette première étude est de décrire le mécanisme cellulaire physiopathologique lié aux défauts transcriptionnels à l'origine de l’atteinte neurodéveloppementale syndromique (pour PTBP1) ou non syndromique (pour PTBP2) par des approches moléculaires fonctionnelles in vitro et in vivo dont le séquençage d'ARNs immunoprécipités (RIP-seq) dans une cohorte d’individus atteints.Dans certains cas, l’analyse génomique met en évidence la présence de variations de structure complexes, pouvant interrompre la séquence d’un gène sensible au dosage, modifier l’activité d’un enhancer ou encore exercer des effets de position sur l'expression génique en altérant les interactions enhancer/gène(s) cible(s). Ces communications moléculaires sont facilitées au sein de domaines d'association topologique (TADs) qui jouent un rôle important dans la régulation transcriptionnelle de manière tissu-spécifique. Par conséquent, toute variation de structure susceptible de réorganiser les TADs (fusion, mélange entre deux TADs ou même création) peut entraîner une altération de l’expression génique. Dans ce contexte, l'objectif du second travail de recherche est de caractériser, au moyen de la capture de conformation de chromosomes à haut débit (Hi-C), les remaniements complexes des patients capables de modifier la structure des TADs. Combinée avec d’autres techniques omiques comme le séquençage longs fragments, les études transcriptomiques ou encore épigénomiques, cette approche permet d'étudier les mécanismes moléculaires sous-jacents sur différents modèles cellulaires dérivés des individus affectés.Ces travaux de recherche mettent en évidence l'impact physiopathologique des variations génétiques ponctuelles et de structure sur les mécanismes de régulation transcriptionnelle et post-transcriptionnelle des gènes cibles et ouvrent la voie à de nouvelles hypothèses biologiques dans le cadre de la recherche translationnelle en pathologie humaineGene expression occurs through the transcription process in the nucleus of eukaryotic cells, which produces RNAs, essential intermediates for protein formation. RNA synthesis and fate are controlled by a complex network of factors, among which are regulatory non-coding DNA sequences that ensure precise spatio-temporal regulation of gene expression and heterogeneous nuclear ribonucleoproteins (hnRNP), able to bind RNA molecules and contributing to their maturation, stability, and localization.The current standard approach for molecular exploration of patients with developmental disorders (DD) and/or intellectual disabilities (ID) uses a combination of chromosomal analysis using DNA microarrays, fragile X testing, exome sequencing, and more recently, genome sequencing to establish a molecular diagnosis. These approaches yield a diagnostic yield of less than 50% for DD/ID. However, the analyses sometimes reveal the presence of variations of uncertain significance in candidate genes not yet implicated in human pathology. Functional tests are then necessary to establish a correct genotype-phenotype correlation. In this way, pathogenic variations have been identified in two candidate genes encoding hnRNPs involved in RNA metabolism: PTBP1 and PTBP2. The aim of this first study is to describe the cellular pathophysiological mechanism related to transcriptional defects causing syndromic (for PTBP1) or non-syndromic (for PTBP2) neurodevelopmental impairment using in vitro and in vivo functional molecular approaches including RNA immunoprecipitation sequencing (RIP-seq) in a cohort of affected individuals.In some cases, genomic analysis identifiy complex structural variations that can disrupt the sequence of a dosage-sensitive gene, alter the activity of an enhancer, or exert position effects on gene expression by altering enhancer/target gene interactions. These molecular communications are facilitated within topological associating domains (TADs), which play an important role in tissue-specific transcriptional regulation. Consequently, any structural variation that reorganizes TADs (fusion, shuffling or even new TAD) can lead to an alteration in gene expression. In this context, the goal of this second research project is to characterize, through high-throughput chromosome conformation capture (Hi-C), the complex rearrangements in patients reorganizing the structure of TADs. Combined with other omic techniques such as long fragment sequencing, transcriptomic or epigenomic analysis, this approach allows the study of the underlying molecular mechanisms on different cellular models derived from affected individuals.These research efforts highlight the physiopathological impact of punctual and structural genetic variations on the transcriptional and post-transcriptional regulatory mechanisms of target genes and pave the way for new biological hypotheses in the context of translational research in human pathology
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Sarkar, Abhishek Kulshreshtha. "Interpreting the role of non-coding genetic variation in human disease." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/112026.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 101-107).
One of the fundamental goals of human genetics is to identify the genetic causes of human disease to ultimately design novel therapeutics. However, two challenges have become readily apparent. First, the majority of genomic regions associated with disease do not implicate protein-altering variants but might instead alter gene regulation, making interpretation and validation more difficult. Second, the genomic regions associated with disease explain a fraction of the variance of associated phenotypes, suggesting human diseases are highly polygenic and that many additional regions remain to be discovered and characterized. Here, we address these challenges by using functional annotation of the human genome spanning diverse data types: epigenomic profiles, gene regulatory circuitry, and biological pathways. We first develop a method to simultaneously select relevant genomic regions not yet associated with disease as well as select relevant functional annotations enriched in those regions. We show that both tissue-specific and shared regulatory regions are enriched for disease associations across eight common diseases. We then characterize specific genetic variants in the selected regions, the gene regulatory elements they reside in, the cellular contexts in which those elements are active, their upstream regulators, their downstream target genes, and the biological pathways they disrupt across eight common diseases. We show that disease associations are additionally enriched in regulatory motifs of relevant transcription factors and in relevant biological pathways. We finally investigate why predicted regulatory elements are enriched in disease-associated variants by framing the problem as Bayesian inference of hyperparameters in a structured sparse regression model. We propose an active sampling method to efficiently explore the hyperparameter space and avoid exponential scaling in the dimension of the hyperparameters. We show in simulation that our method can distinguish between possible explanations of the observed enrichments, and we characterize potential biases in the estimates. Together, our results can help guide the development of new models of disease and gene regulation and discovery of biologically meaningful, but currently undetectable regulatory loci underlying a number of common diseases.
by Abhishek Sarkar.
Ph. D.
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Lomelin, David. "Using human genetic variation to predict functional elements in non-coding genomic regions." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390057.
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Barcons, Simon Anna. "Clonally variant non-coding RNA family and its role in Plasmodium falciparum antigenic variation." Electronic Thesis or Diss., Sorbonne université, 2019. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2019SORUS042.pdf.
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La variation antigénique est un mécanisme d'évasion immunitaire utilisé par le parasite du paludisme Plasmodium falciparum pour établir une infection prolongée. Il empêche la clairance parasitaire en modifiant l’expression des antigènes variables de surface, codés par la famille de gènes appelés « var », comprenant 60 membres. Au stade sanguin, les parasites expriment les gènes var d'une manière mutuellement exclusive, avec un seul gène var actif à un moment donné, permettant ainsi au parasite d’échapper au système immunitaire qui reste naïf envers une sous-population de parasites. Malgré les multiples facteurs connus pour être impliqués dans l’inactivation des gènes var par défaut, tels que les modifications des histones et l'architecture nucléaire, un facteur d'activation spécifique n'a pas encore été identifié. Dans ce travail de thèse, une famille d'ARNnc riche en GC, transcrite par l’ARN polymérase III, a été explorée comme facteur régulateur candidat à l'activation des gènes var. La famille des ARNnc riches en GC se compose de 15 membres homologues, positionnés de façon adjacente aux gènes var situés au centre du chromosome. L'analyse d’expériences de FISH de l'ARN a révélé que l'ARNnc riche en GC cible le site d'expression du gène var en trans. De plus, la surexpression d'un membre des ARNnc riches en GC surpasse l'expression mutuellement exclusive des gènes var et induit la transcription d'un sous-ensemble spécifique de gènes var. Nous avons développé un système de dead Cas9 ciblant la transcription de tous les membres riches en GC. Il est frappant de constater que le blocage transcriptionnel de tous les membres riches en GC par interférence CRISPR entraîne une régulation à la baisse de la transcription des gènes var à un niveau basal. Nos données confirment le rôle de cet ARNnc dans le processus d'activation des gènes var. De plus, nous montrons que la famille de gènes de l'ARNnc riche en GC est une variante clonale, ce qui indique que cela peut déterminer les taux de commutation et l'ordre de commutation de la famille de gènes var. Nous avons développé un protocole ChIRP (chromatin isolation by RNA purification) robuste qui nous a permis d'identifier des régions potentielles de liaison à la chromatine et des partenaires interagissant avec cette famille d'ARNnc. La validation de plusieurs protéines candidates prometteuses obtenues par spectrométrie de masse est en cours. De plus, nous avons cherché à savoir si les loci géniques de ces ARNnc présentent des interactions à longue distance, à l'aide d'une technique de capture de conformation chromosomique. Nous avons obtenu la preuve que les loci géniques de ces ARNnc présentent des interactions à longue distance entre eux et peuvent donc jouer un rôle dans l'organisation spatiale des foci nucléaires. Cette étude fournit le premier lien fonctionnel entre la transcription de l’ARN Pol III et Pol II dans le processus d'expression mutuellement exclusive des gènes de virulence. De plus, l'exploration de cet ARNnc est une étape clé dans le dévoilement du processus d'évasion immunitaire et de la pathogenèse de P. falciparumAntigenic variation is an immune evasion mechanism used by the malaria parasite Plasmodium falciparum to establish prolonged infection. It prevents parasite clearance by switching the display of variant surface antigens encoded by the 60-member var gene family. Blood stage parasites express var genes in a mutually exclusive manner, with a single var active at a given time, ensuring that the immune system remains naive to a parasite sub-population. Despite multiple factors known to be involved in default var gene silencing, such as histone modifications and nuclear architecture, a specific activation factor has not been identified yet. In this thesis work, a polymerase III-transcribed family of GC-rich ncRNA was explored as a candidate regulatory factor of var gene activation. The GC-rich ncRNA family consists of 15 homologous members positioned adjacent to chromosome-central var genes. RNA FISH analysis revealed that the GC-rich ncRNA is targeted to the var expression site in trans. Overexpression of one GC-rich ncRNA member overrules singular var expression and induces transcription of a specific subset of var genes. We developed a dead Cas9 system aiming to target transcription of all GC-rich members. Strikingly, transcriptional blocking of all GC-rich members by CRISPR interference results in down-regulation of var transcription to background levels. Our data support a role of this ncRNA in the activation process of var genes. Moreover, we show that the GC-rich ncRNA gene family is clonally variant, indicating that this may determine switch rate and switch order of the var gene family. We developed a robust ChIRP (chromatin isolation by RNA purification) protocol that allowed us to identify potential chromatin binding regions and interacting partners of this ncRNA family. The validation of several promising candidate proteins obtained my mass spectrometry is ongoing. Furthermore, we investigated whether the gene loci of these ncRNAs display long-range interactions using a chromosome conformation capture technique. We obtained evidence that the gene loci of these ncRNAs display long-range interactions between them and can thus play a role in nuclear spatial foci organization. This study provides the first functional link between Pol III and Pol II transcription in the process of mutually exclusive expression of virulence genes. Moreover, exploring this ncRNA is a key step in unveiling the process of immune evasion and pathogenesis of P. falciparum
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Christodoulou, Zoe. "An analysis of non-coding RNAs in Plasmodium falciparum and their potential role in antigenic variation." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:60ea27e2-1129-4914-8abd-cfad018e0353.
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A major virulence factor of the human malaria parasite Plasmodium falciparum is Plasmodium falciparum erythrocyte membrane protein 1(PfEMP-1). This protein is inserted into the erythrocyte membrane, giving cytoadherence properties. A family of genes called var, located sub-telomerically and in chromosome central clusters encode this protein. Var genes are expressed in a mutually exclusive manner, how this is controlled is unclear. A non-coding RNA (ncRNA) termed the GC-rich element (GRE) had been identified that is only located at the central clusters and is transcribed throughout the parasite lifecycle. A screen of the P. falciparum genome for novel ncRNAs identified ncRNAs from known classes. Novel transcripts were identified, but none in the proximity of var genes. We have investigated the role of the GRE in var gene regulation. A set of qRT-PCR primers have been designed and tested to follow var gene expression in the HB3 isolate, these are not cross-reactive with a published set for the 3D7 isolate. Alterations were made to the 3D7 set to remove cross-reactivity with HB3. Var gene expression was studied in 31 HB3 clones and progeny of the 3D7xHB3 genetic cross. Following var switching over five months in eleven HB3 clones showed that all of the clones ended up expressing var genes from the same central cluster on chromosome 4. GRE Transcription in these clones is linked to a specific class of var gene. Transcription from a single GRE locus occurs only when a var gene of the central UpsC class is expressed from the same cluster. Expression of other classes of var gene gives multiple transcripts from different GRE loci. Investigations into the in vitro binding properties of the GRE revealed an RNA:protein complex that can be resolved by electrophoresis. Proteomic analysis of the complex revealed predominantly ribosome proteins and translation factors.
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Li, Jia. "Identifier les variations conduisant au cancer dans le génome non codant et du transcriptome." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS161/document.
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L'annotation fonctionnelle de mutations somatiques est un point focal des études de génomique du cancer. Jusque récemment, la recherche s'est concentré sur des mutations dans la fraction codante du génome, pour lesquelles de puissants outils bioinformatiques ont été développés afin de distinguer des mutations délétères des mutations neutres. On identifie un nombre croissant de variants associés à des maladies dans le génome non-codant. L'interprétation des mutations non-codantes dans le cancer est donc devenue une tâche urgente. Des projets de grande envergure tels que ENCODE ont rendu possible l'interprétation fonctionnelle de variants dans les cancers. Plusieurs programmes ont été produits sur la base de ces informations fonctionnelles. Ces outilssont encore limités, notamment, une bas précision de la prédiction, le manque d'information de la mutation de cancer et biais de constatation importante. Dans le chapitre 2 de cette thèse, pour interpréter fonctionnellement les mutations non-codantes dans les cancers, nous avons développé deux modèles de forêts aléatoires indépendants, appelées SNP et SOM. Compte tenu de la combinaison de caractéristiques fonctionnelles à une position donnée du génome, le modèle SNP prédit la fraction de SNP rares (une mesure de la sélection négative), et le modèle SOM prédit la densité de mutations somatiques attendue à cette position. Nous avons appliqué nos deux modèles pour évaluer des clinvariant and HGMD variants asociés à des maladies, et un ensemble de SNP-contrôle aléatoires. Les résultats ont montré que les variants associés à des maladies ont des scores plus élevés que les SNP-contrôle avec le modèle SNP et inférieures avec le modèle SOM, confortant notre hypothèse selon laquelle la sélection négative, telle que mesurée par fraction de SNP rares et de densité de mutation somatiques, nous informe sur l'impact fonctionnel des mutations tumorales dans le génome non-codant. Jusqu'à présent, les chercheurs ont surtout considéré les gènes protéiques comme critiques dans l'initiation et la progression des cancers. Toutefois, des preuves récentes ont montré que les ARN non-codants, en particulier les lncRNAs, sont activement impliqués dans divers processus de cancer. Un chapitre de cette thèse est consacré à cette classe de transcripts non codants. Comme pour les gènes codants, il pourrait exister un grand nombre de lncRNAs driver de cancer. Le développement d'outils bioinformatiques pour identifier et hiérarchiser les lncRNA et autres ARN non-codants est devenu un important objet de recherche en oncologie.La dernière partie de cette thèse est consacrée à la mise en œuvre de méthodes pour découvrir des éléments non-codants potentiellement driver de cancer. Nous avons d'abord appliqué trois outils tierces, CADD, funSeq2, GWAVA, ainsi que nos modèles SNP et SOM, pour évaluer l'impact des mutations non-codantes dans tout le génome. Pour chaque locus, nous calculons la moyenne des scores de tous les variants observés à l'aide de l'un des modèles, et nous prenons au hasard le même nombre de variants et calculons leur score moyen 1 million de fois pour former une distribution nulle et obtenir une P-valeur pour ce locus. Pour valider notre hypothèse et notre modèle de permutation, nous avons testé ce système sur 452 gènes codants et 61 lncRNA liés au cancer, en utilisant des données de mutation somatique de cancer du foie, cancer du poumon, CLL et mélanome. Nous avons constaté que les lncRNAs et gènes codants associés au cancer avaient des valeurs-P significativement plus faibles que l'ensemble de lncRNAs et gènes codant. Appliquer ce test de permutation à des lncRNAs avec cinq systèmes de notation différents nous a permis de prioriser les centaines de candidats potentiellement liés au cancer.Ces candidats peuvent maintenant être soumis à validation expérimentaleFunctional annotation of somatic mutations have been a consistent hotspot of cancer genomics studies. In the past, researchers preferentially focused on mutations in the coding fraction of the genome, for which ample bioinformatics tools were developed to distinguish cancer-driver mutations from neutral ones. In recent years, as an increasing number of variants were being identified as disease-associated in the non-coding genome, interpreting non-coding cancer mutations has become an urgent task. The completion of large scale projects such as ENCODE, has made functional interpretation of cancer variants achievable, and several programs were produced based on this functional information. However, there still exists some limitations as to these prediction tools, such as low prediction accuracy, lack of cancer mutation information and significant ascertainment bias. In chapter 2 of this thesis, in order to functionally interpret non-coding mutations in cancer, we developed two independent random forest models, referred to as SNP and SOM. Given a combination of features at a given genome positions, the SNP model predicts the expected fraction of rare SNPs (a measure of negative selection), and the SOM model predicts the expected mutation density at this position. We applied our two models to score these non-coding disease-associated clinvariant and HGMD variants and a set of random control SNPs. Results showed that disease-associated variants were scored higher than control SNPs with the SNP model and lower than control SNPs with the SOM model, supporting our hypothesis that purifying selection as measured by fraction of rare SNPs and mutation density is informative for the evaluation of the functional impact of cancer mutations in the non-coding genome. In the past, researchers have preferentially considered protein-coding genes as critical to the initiation and progression of cancers. However, recent evidences have shown that ncRNAs, in particular lncRNAs, are actively implicated in various cancer processes. A chapter of this thesis is devoted to this class of non-coding transcripts. Similar to protein coding genes, there might be a large number of lncRNAs with cancer-driving functions. The development of bioinformatics tools to prioritize them has become a new focus of research for computational oncologists.The last part of this thesis is devoted to the implementation of methods for discovering potential cancer-driving non-coding elements in lncRNA and protein-coding genes. We applied three scoring tools, CADD, funSeq2, GWAVA, together with our SNP and SOM scoring systems to prioritize cancer-associated elements using a permutation-based algorithm. For each locus, we compute the average score of all observed variants using one of the models, and we randomly take the same number of variants and compute their average score 1 million times to form a null distribution and obtain a P value for this locus. To validate our hypothesis and permutation model, we tested this system on 61 cancer-related lncRNA and 452 cancer genes using somatic mutation data from liver cancer, lung cancer, CLL and melanoma. We observed that both cancer lncRNAs and protein-coding genes had significantly lower average P values than total lncRNAs and protein-coding genes in all cases. Applying the permutation test to lncRNAs with five different scoring systems enabled us to prioritize hundreds to thousands of cancer-related lncRNA candidates. These candidates can be used for future experimental validation
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Lalaouna, David. "Role d' ARN non codants régulateurs dans l' adaptation de Pseudomonas brassicacearum à la rhizosphère et aux fluctuations de l' environnement." Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4006.
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Pseudomonas brassicacearum a la particularité de générer une diversité intraclonale aussi bien in vitro qu'en conditions naturelles dans la rhizosphère de plantes. Ce phénomène de variation phénotypique commun chez les bactéries est un processus d'adaptation aux environnements changeants. Des données de transcriptomique issues de puces à ADN, contenant aussi bien des séquences codantes que non codantes, nous ont permis d'identifier les gènes dont l'expression est altérée et surtout de relier ce phénomène à l'expression d'ARN non codants régulateurs (ARNnc) de type Rsm qui sont sous le contrôle du système à deux composants GacS/GacA. Nous avons montré que des mutations ponctuelles dans les gènes gacS ou gacA sont à l'origine de cette variation phénotypique et que l'expression de l'un des trois gènes rsmX, rsmY ou rsmZ permet de restaurer le phénotype de la souche sauvage. L'importance de ces ARNnc dans la survie de la bactérie aux fluctuations de son environnement est dénotée par la duplication de rsmX en un gène que nous avons nommé rsmX-2, dont la fonction a été validée. Nos données suggèrent une activation exclusive des gènes rsmX-1 et rsmX-2 par GacA et l'intervention de régulateurs additionnels dans le cas de rsmY et rsmZ. Au vu de la redondance fonctionnelle de ces quatre ARNnc, nous avons investigué leur niveau d'expression et leur stabilité dans différentes conditions de culture et montré des différences pour les quatre ARNnc. En réponse à une carence en nutriments, l'expression des ARNnc Rsm est fortement activée et atteint son maximum quand le ppGpp est détecté dans le milieu, suggérant un lien entre le système Gac/Rsm et la réponse « stringente »The plant-beneficial bacterium Pseudomonas brassicacearum forms phenotypic variants in vitro as well as in planta during root colonisation under natural conditions. Transcriptome analysis of typical phenotypic variants using microarrays containing coding as well as non-coding DNA fragments showed differential expression of several genes relevant to secondary metabolism and of the small non-coding RNA (ncRNA) genes rsmX, rsmY and rsmZ, which was characterized by down-regulation. Naturally occurring mutations in the GacS/GacA two-component system accounted for phenotypic switching. The importance of these ncRNAs in the survival of the bacteria to changing environments is denoted by the duplication of rsmX gene, which we called rsmX-2 and whose function has been validated. Our data suggest an exclusive activation of rsmX-1 and rsmX-2 genes by GacA and the involvement of additional regulators in the case of rsmY and rsmZ. Given the functional redundancy of these ncRNAs, we investigated their expression level and stability in different culture conditions and showed differences for the four ncRNAs. In response to nutrient depletion, the four ncRNAs expression is strongly activated and reaches its maximum when the ppGpp is detected in bacterial cells, suggesting a link between the Gac/Rsm system and the "stringent" response. Determining the level of each Rsm ncRNA, which is defined by a balance between synthesis and degradation of each transcript, shows the maintenance of a very important pool of RsmZ compared to other ncRNAs
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Diffendall, Gretchen. "Deciphering the role of an RNA Pol III-transcribed non-coding RNA in Plasmodium falciparum." Electronic Thesis or Diss., Sorbonne université, 2022. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2022SORUS443.pdf.
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Le parasite protozoaire Plasmodium falciparum est l'agent causal de la forme la plus mortelle de paludisme humain. Ce pathogène utilise l'expression monoallélique de molécules d'adhésion de surface variantes, codées par la famille de gènes var, pour échapper au système immunitaire de l'hôte et provoquer une pathogenèse. On ne sait toujours pas comment l'activation du gène var fonctionne au niveau moléculaire et si des facteurs environnementaux peuvent moduler l'expression du gène var. Notre laboratoire a montré qu'une famille de gènes d'ARN non codants transcrits par Pol III, appelée RUF6, agit comme un trans-activateur des gènes var. Une association physique entre l'ARNnc RUF6 transcrit et le locus du gène var actif a été observée par FISH. La répression transcriptionnelle de tous les RUF6 par une stratégie d'interférence CRISPR spécifique a entraîné une régulation négative de la transcription de toute la famille des gènes var, suggérant une fonction potentielle de type amplificateur pour l'expression des gènes var. Une compréhension de la façon dont l'ARNnc RUF6 médie l'activation du gène var fait défaut. Ici, nous avons développé un protocole robuste de découverte protéomique dirigée par l'ARN (ChIRP-MS) pour identifier les interactions in vivo des protéines ARNnc RUF6. Des oligonucléotides antisens biotinylés ont été utilisés pour purifier l'interactome d'ARNnc RUF6. La spectrométrie de masse a identifié plusieurs protéines enrichies de manière unique qui sont liées à la transcription génique, telles que les sous-unités d'ARN Pol II, les protéines d'assemblage des nucléosomes et un homologue de la Dead-Box Helicase 5 (DDX5). La purification par affinité de PfDDX5 a identifié plusieurs protéines trouvées à l'origine par notre protocole RUF6-ChIRP, validant la robustesse de la technique pour l'identification des interactomes d'ARNnc chez P. falciparum. Le déplacement inductible de PfDDX5 nucléaire a entraîné une importante régulation à la baisse du gène var actif. Notre travail identifie un complexe protéique RUF6 ARNnc qui interagit avec l'ARN Pol II pour soutenir l'expression du gène var. Nous postulons que l'hélicase DDX5 peut résoudre les structures secondaires G-quadruplex hautement enrichies en gènes var pour faciliter l'activation et la progression de la transcription. De plus, nous découvrons des facteurs environnementaux qui déclenchent une régulation négative de la transcription du gène var. Nous observons que la privation d'isoleucine et les concentrations élevées de MgCl2 dans le milieu inhibent les gènes transcrits par l'ARN polymérase III. Il est important de noter que cela inclut une famille de gènes ARNnc régulateurs spécifiques de P. falciparum (codée par la famille de gènes RUF6) qui est un régulateur clé de l'activation du gène var. Nous avons identifié un gène homologue à l'eucaryote Maf1 hautement conservé, en tant qu'effecteur négatif de la transcription de l'ARNnc RUF6. Des concentrations élevées de MgCl2 ont entraîné un déplacement de PfMaf1 cytoplasmique vers le compartiment nucléaire. Nous avons utilisé un système de dégradation inductible des protéines pour montrer que les stimuli externes dépendent de PfMaf1 pour déclencher une expression plus faible des gènes RUF6. Nos résultats indiquent une voie indépendante de TOR qui répond aux changements de l'environnement et réprime la transcription Pol III. Ce travail fournit des informations conceptuelles nouvelles et importantes sur la répression de la virulence du parasite dépendante de PfMaf1 qui peuvent être très pertinentes pour établir la persistance subclinique du parasite pendant la saison sèche. Pris ensemble, ces résultats aident à mieux comprendre la fonction et la régulation d'un ARNnc impliqué dans la régulation de la variation antigénique et de la pathogenèse chez P. falciparum. Notre validation de la technique ChIRP-MS permet de futures études dans l'identification des protéines de liaison à l'ARN pour les ARNnc dont la fonction [...]The protozoan parasite Plasmodium falciparum is the causative agent of the deadliest form of human malaria. This pathogen uses monoallelic expression of variant surface adhesion molecules, encoded by the var gene family, to evade the host immune system and cause pathogenesis. It remains unclear how monoallelic expression of var gene activation works at the molecular level and if environmental factors can modulate var gene expression. Our laboratory showed a Pol III transcribed GC-rich non-coding RNA gene family, termed RUF6, acts as a trans-activator of var genes. A physical association between the transcribed RUF6 ncRNA and the active var gene locus was observed through FISH. Transcriptional repression of all RUF6 by a specific CRISPR interference strategy resulted in transcriptional down regulation of the entire var gene family, suggesting a potential enhancer-like function to var gene expression. An understanding of how RUF6 ncRNA mediates var gene activation is lacking. Here we developed a robust RNA-directed proteomic discovery (ChIRP-MS) protocol to identify in vivo RUF6 ncRNA protein interactions. Biotinylated antisense oligonucleotides were used to purify the RUF6 ncRNA interactome. Mass spectrometry identified several uniquely enriched proteins that are linked to gene transcription such as RNA Pol II subunits, nucleosome assembly proteins, and a homologue of the Dead-Box Helicase 5 (DDX5). Affinity purification of PfDDX5 identified several proteins originally found by our RUF6-ChIRP protocol, validating the robustness of the technique for the identification of ncRNA interactomes in P. falciparum. Inducible displacement of nuclear Pf-DDX5 resulted in the significant down-regulation of the active var gene. Our work identifies a RUF6 ncRNA protein complex that interacts with RNA Pol II to sustain var gene expression. We postulate that DDX5 helicase may resolve G-quadruplex secondary structures highly enriched in var genes to facilitate transcriptional activation and progression. Furthermore, we discovered environmental factors that trigger downregulation of var gene transcription. We observe that isoleucine starvation and high MgCl2 concentrations in the medium inhibit RNA Polymerase III transcribed genes. Importantly, this includes a P. falciparum-specific regulatory ncRNA gene family (encoded by the RUF6 gene family) that is a key regulator in var gene activation. We identified a homologous gene to the highly conserved eukaryotic Maf1, as a negative effector of RUF6 ncRNA transcription. Elevated MgCl2 concentrations led to a shift of cytoplasmic PfMaf1 to the nuclear compartment. We used an inducible protein degradation system to show that external stimuli depend on PfMaf1 to trigger lower expression of RUF6 genes. Our results point to a TOR independent pathway that responds to changes in the environment and represses Pol III transcription. This work provides new and important conceptual insights into PfMaf1-dependent repression of parasite virulence that may be highly relevant for establishing subclinical parasite persistence in the dry season. Taken together, these results help to better understand the function and regulation of a ncRNA involved in regulating the antigenic variation and pathogenesis in P. falciparum. Our validation of the ChIRP-MS technique allows for future studies in identifying RNA-binding proteins for ncRNAs whose function remains to be fully characterized
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Lundmark, Per Erik. "Genetic and Genomic Analysis of DNA Sequence Variation." Doctoral thesis, Uppsala universitet, Molekylär medicin, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-158486.
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The studies in this thesis describe the application of genotyping and allele specific expression analysis to genetic studies. The role of the gene NPC1 in Triglyceride metabolism was explored in mouse models and in humans on the population level in study I. NPC1 was found to affect hepatic triglyceride metabolism, and to be relevant for controlling serum triglyceride levels in mice and potentially in humans. In study II the utility of the HapMap CEU samples was investigated for tagSNP selection in six European populations. The HapMap CEU was found to be representative for tagSNP selection in all populations while allele frequencies differed significantly in the sample from Kuusamo, Finland. In study III the power of Allele specific expression as a tool for the mapping of cis-regulatory variation was compared to standard eQTL analysis, ASE was found to be the more powerful type of analysis for a similar sample size. Finally ASE mapping was applied to regions reported to harbour long non-coding RNAs and associated SNPs were compared to published trait-associations. This revealed strong cis-regulatory SNPs of long non-coding RNAs with reported trait or disease associations.
Books on the topic "Non coding variations"
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Yang, Jin, Pei Han, Wei Li, and Ching-Pin Chang. Epigenetics and post-transcriptional regulation of cardiovascular development. Edited by José Maria Pérez-Pomares, Robert G. Kelly, Maurice van den Hoff, José Luis de la Pompa, David Sedmera, Cristina Basso, and Deborah Henderson. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198757269.003.0032.
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Cardiac organogenesis requires the control of gene expression at distinct developmental windows in order to organize morphogenetic steps in the correct sequence for heart development. This is facilitated by concerted regulation at three levels: chromatin, transcription, and post-transcriptional modifications. Epigenetic regulation at the chromatin level changes the chromatin scaffold of DNA to regulate accessibility of the DNA sequence to transcription factors for genetic activation or repression. At the genome, long non-coding RNAs work with epigenetic factors to alter the chromatin scaffold or form DNA-RNA complexes at specific genomic loci to control the transcription of genetic information. After RNA transcription, the expression of genetic information can be further modified by microRNAs. Each layer of gene regulation requires the participation of many factors, with their combinatorial interactions providing variations of genetic expression at distinct pathophysiological phases of the heart. The major functions of chromatin remodellers and non-coding RNAs are discussed.
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Broad-scale variation in human genetic diversity levels is predicted by purifying selection on coding and non-coding elements. [New York, N.Y.?]: [publisher not identified], 2021.
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Rucker, James J. H., and Peter McGuffin. Copy Number Variation in Neuropsychiatric Disorders. Edited by Turhan Canli. Oxford University Press, 2013. http://dx.doi.org/10.1093/oxfordhb/9780199753888.013.005.
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It has long been known that the human genome is subject to deletion and duplication of genetic material by various molecular mechanisms. Until recently, such events were assumed to be relatively rare phenomena. It is now known that submicroscopic deletions or duplications calledcopy number variants(CNVs) are a major source of genomic variation. Rare CNVs (defined as occurring in less than 1 percent of the population) have been implicated in schizophrenia and autism. Measured in terms of odds ratios, individual CNVs have been shown to have large effects, some increasing the risk of disorder several-fold. But they are incompletely penetrant, no one CNV is either necessary or sufficient to cause the disorder. The findings are less clear-cut with bipolar disorder but, here, too, rare CNVs probably play a role. In unipolar depression, initial evidence suggests an overall increase in rare CNVs that disrupt exons, the coding regions of genes.
Book chapters on the topic "Non coding variations"
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Koksoy, Hale. "The Role of Genetics and Epigenetics in Diabetes Progress." In Current Multidisciplinary Approach to Diabetes Mellitus Occurrence Mechanism, 1–13. Istanbul: Nobel Tip Kitabevleri, 2023. http://dx.doi.org/10.69860/nobel.9786053359104.1.
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Genetics and epigenetics play critical roles in the progression and manifestation of diabetes mellitus. Genetic factors contribute significantly to an individual’s susceptibility to developing diabetes, influencing aspects such as insulin production, glucose metabolism, and pancreatic function. Variations in genes associated with insulin secretion (e.g., TCF7L2) and insulin sensitivity (e.g., IRS1) can predispose individuals to type 2 diabetes. Additionally, epigenetic mechanisms, which involve modifications in gene expression without altering the underlying DNA sequence, are increasingly recognized as key players in diabetes pathogenesis. Factors such as DNA methylation, histone modifications, and non-coding RNA regulation can influence gene activity related to glucose homeostasis and insulin signaling pathways. Understanding the interplay between genetic predisposition and epigenetic regulation provides valuable insights into the heterogeneous nature of diabetes mellitus and offers potential avenues for personalized treatment strategies and disease management.
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Heers, Josef, Christoph Schnörr, and H. Siegfried Stiehl. "A Class of Parallel Algorithms for Nonlinear Variational Segmentation: A preprocess for robust feature-based image coding." In Noblesse Workshop on Non-Linear Model Based Image Analysis, 146–51. London: Springer London, 1998. http://dx.doi.org/10.1007/978-1-4471-1597-7_23.
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Schulze-Bahr, Eric. "Basic principles of genetic disease." In ESC CardioMed, 669–71. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198784906.003.0148.
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The human genome consists of approximately 3 billion (3 × 109) base pairs of DNA (around 20,000 genes), organized as 23 chromosomes (diploid parental set), and a small mitochondrial genome (37 genes, including 13 proteins; 16,589 base pairs) of maternal origin. Most human genetic variation is natural, that is, common or rare (minor allele frequency >0.1%) and does not cause disease—apart from every true disease-causing (bona fide) mutation each individual genome harbours more than 3.5 million single nucleotide variants (including >10,000 non-synonymous changes causing amino acid substitutions) and 200–300 large structural or copy number variants (insertions/deletions, up to several thousands of base-pairs) that are non-disease-causing variations and scattered throughout coding and non-coding genomic regions.
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Alhamdan, Rana. "Would Non-coding RNA Resolve the Polycystic Ovary Syndrome (PCOS) Puzzle?" In Polycystic Ovary Syndrome - Symptoms, Causes and Treatment [Working Title]. IntechOpen, 2024. http://dx.doi.org/10.5772/intechopen.114387.
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Polycystic ovary syndrome (PCOS) is the most common endocrine heterogeneous reproductive disorder. This metabolic disease affects around 5–10% of women and accounts for 75% of anovulatory infertility all over the world. The complexity of the disease as manifested by the involvement of multiple underlying mechanisms and the lack of specific and sensitive biomarkers, make it difficult to timely manage and treat the disease. Remarkably, genetic, epigenetics, and environmental variations may contribute considerably to the pathogenicity of PCOS. Recent investigations indicated that non-coding RNAs (ncRNA) were involved in the occurrence and development of PCOS. Thus, this chapter aimed to summarize the current knowledge around the expression and dysregulation of ncRNA in human PCOS.
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D. Magar, Nakul, Priya Shah, K. Harish, Tejas C. Bosamia, Kalyani M. Barbadikar, Yogesh M. Shukla, Amol Phule, et al. "Gene Expression and Transcriptome Sequencing: Basics, Analysis, Advances." In Gene Expression [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.105929.
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Gene expression studies are extremely useful for understanding a broad range of biological, physiological, and molecular responses. The techniques for gene expression reflect differential patterns of gene regulation and have evolved with time from detecting one gene to many genes at a time laterally. Gene expression depends on the spatiotemporal expression in a particular tissue at a given time point and needs critical examination and interpretation. Transcriptome sequencing or RNA-seq using next-generation sequencing (short and long reads) is the most widely deployed technology for accurate quantification of gene expression. According to the biological aim of the experiment, replications, platform, and chemistries, propelling improvement has been demonstrated and documented using RNA-seq in plants, humans, animals, and clinical sciences with respect to gene expression of mRNA, small non-coding, long non-coding RNAs, alternative splice variations, isoform variations, gene fusions, single-nucleotide variants. Integrating transcriptome sequencing with other techniques such as chromatin immunoprecipitation, methylation, genome-wide association studies, manifests insights into genetic and epigenetic regulation. Epi-transcriptome including RNA methylation, modification, and alternative polyadenylation events can also be explored through long-read sequencing. In this chapter, we have presented an account of the basics of gene expression methods, transcriptome sequencing, and the various methodologies involved in the downstream analysis.
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Iqbal, Nashra, Priyanka Vishwakarma, and Vidya Meenakshi. "NEXT GENERATION SEQUENCING FOR CANCER DIAGNOSIS." In Futuristic Trends in Biotechnology Volume 3 Book 21, 137–51. Iterative International Publishers, Selfypage Developers Pvt Ltd, 2024. http://dx.doi.org/10.58532/v3bkbt21p1ch11.
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The development of sequencing of the next generation (NGS) technology has facilitated the study of cancer. Massive parallel sequencing made possible by NGS provides for the most thorough genomic analysis of tumors. Different NGS methods focus on DNA and RNA analysis. Genome on the whole part, whole-exome, and targeted DNA sequencing are several classes of sequencing that concentrate on a subdivision of genetic factors that may be related to a certain condition. Alternative gene-spliced transcripts, small and long non-coding RNAs, mutations/single-nucleotide polymorphisms, post-transcriptional alterations, gene fusions and variations in genetic expression are all more easily found using RNA sequencing. The majority of NGS implementations are in the realm of cancer research, but recently, NGS technology has revolutionized molecular diagnosis of cancer because of the many benefits it provides over conventional approaches.
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Ferguson, Rex. "Secretions." In Identification Practices in Twentieth-Century Fiction, 119–58. Oxford University Press, 2021. http://dx.doi.org/10.1093/oso/9780198865568.003.0004.
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DNA profiling, in which individual being is identified by its cellular structures, was first developed by the geneticist Alec Jeffreys in the 1980s. That this source of identity also forms the instructions through which living organisms are generated has complicated profiling’s place in the cultural imaginary of the late twentieth century. So, while profiling actually deals only in non-coding regions of the genome—matter often referred to as ‘junk DNA’—the significance of DNA as a substance of forensic analysis, in the late twentieth century imaginary, is its resonance as the apparent blueprint of existence. The notable features that this blurring of concepts brings about include a conceptualization of identity as a mass of information; notions to do with codes and coding; the presence of the body in the fluids which spill beyond its bounds; and a sense of the body as an archive of heredity and primitivism. In writing specifically about genetic research, Richard Powers’s The Gold Bug Variations (1991) serves a dual function in this chapter, as both an explicatory document and thematic example. But the more substantive analysis is reserved for the work of J. G. Ballard which, from its science fiction origins in novels such as The Drowned World (1962), through the controversial era of Crash (1973), to its trilogy of autobiographical texts (Empire of the Sun (1984), The Kindness of Women (1991), and Miracles of Life (2008)) articulates a form of identity that has close, though often oblique, affinities with all the most prominent features of DNA profiling.
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Koinova, Maria. "The Microfoundations." In Diaspora Entrepreneurs and Contested States, 61–94. Oxford University Press, 2021. http://dx.doi.org/10.1093/oso/9780198848622.003.0003.
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Chapter 3 is the second theoretical chapter focusing on the individual-level perspective on diaspora mobilizations and the two-level typological theory. How do the four types of diaspora entrepreneurs—Broker, Local, Distant, and Reserved—interact with exogenous factors? How do these interactions lead to different modes of contention and channelling of interest through host-states, transnational networks, and supranational organizations? The two-level typological theory is unpacked through each of its constitutive elements: (1) diaspora entrepreneurs, (2) exogenous factors affecting them, and (3) contentiousness and channelling of their mobilizations, through their conjunctural variations. The chapter first conceptualizes diaspora entrepreneurs’ socio-spatial linkages and the typology developed through novel relational coding. Building on earlier work in International Relations, the Politically Relevant Environment (PRE) is discussed next. It is useful to theoretically narrow down the numerous factors affecting diaspora entrepreneurs in a particular context, namely when they are socio-spatially contiguous and affecting existing grievances related to conflict-generated identities of diaspora entrepreneurs. The chapter further theorizes about causal mechanisms and the nine causal pathways emerging through interactions between diaspora entrepreneurs and PRE factors such as host-land foreign policies, homeland governments, parties, non-state actors, critical events, and limited global influences. Four non-contentious pathways, four characterized by a dual-pronged approach, and one more contentious are presented.
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Creissels, Denis. "Transitive coding and valency." In Transitivity, Valency, and Voice, 275–316. Oxford University PressOxford, 2024. http://dx.doi.org/10.1093/9780198899594.003.0007.
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Abstract The topic of this chapter is transitivity prominence, i.e., the extent to which languages make use of transitive coding to encode events that are not prototypically transitive. Section 7.1 examines this question for semantically bivalent verbs, for which transitive coding constitutes the default coding frame. Section 7.2 analyzes the variation in the coding frames of trivalent verbs, whose participant structure can generally be analyzed as including an agent, a transferee, and a goal. As a rule, trivalent verbs select transitive coding frames, but there is important cross-linguistic variation in the choice between double-P constructions, indirective alignment, and secundative alignment. Section 7.3 analyzes the possible uses of the transitive construction in clauses projected by semantically monovalent verbs.
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Nei, Masatoshi, and Sudhir Kumar. "Evolutionary Change of DNA Sequences." In Molecular Evolution and Phylogenetics, 33–50. Oxford University PressNew York, NY, 2000. http://dx.doi.org/10.1093/oso/9780195135848.003.0003.
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Abstract The evolutionary change of DNA sequences is more complicated than that of protein sequences, because there are various types of DNA regions such as protein-coding regions, noncoding regions, exons, intrans, flanking regions, repetitive DNA sequences, and insertion sequences. It is therefore important to know the type and function of the DNA region under investigation. As mentioned in chapter 1, the mutational change of DNA varies extensively with DNA region. Even if we consider protein coding regions alone, the patterns of nucleotide substitution at the first, second, and third codon positions are not the same. Furthermore, some regions are subject to natural selection more often than other regions, and this also contributes to variation of evolutionary pattern among different regions of DNA.
Conference papers on the topic "Non coding variations"
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"Interpreting non-coding genome variation with DNA sequence motifs." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/bgrs/sb-2022-038.
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"Interpreting non-coding genome variation with DNA sequence motifs." In Bioinformatics of Genome Regulation and Structure/Systems Biology (BGRS/SB-2022) :. Institute of Cytology and Genetics, the Siberian Branch of the Russian Academy of Sciences, 2022. http://dx.doi.org/10.18699/sbb-2022-038.
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Holik, A., and S. Ossowski. "PO-348 The other 98%: making sense of non-coding variation." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.378.
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Baross, Stephanie, Simon Williams, Kathryn Hentges, Andrew Sharrocks, and Bernard Keavney. "BS54 Variation in cardiac long non-coding rnas in congenital heart disease." In British Cardiovascular Society Annual Conference ‘Digital Health Revolution’ 3–5 June 2019. BMJ Publishing Group Ltd and British Cardiovascular Society, 2019. http://dx.doi.org/10.1136/heartjnl-2019-bcs.215.
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Umu, SU, R. Lyle, H. Langseth, and TB Rounge. "PO-096 Natural variation in serum small non-coding RNAs – potential biomarkers of cancer." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.623.
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Buchsbaum, Gershon. "Optimal coding of spatiochromatic information in the retina." In OSA Annual Meeting. Washington, D.C.: Optica Publishing Group, 1986. http://dx.doi.org/10.1364/oam.1986.tuf2.
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Natural visual stimuli are multidimensional signals encompassing parameters of space, time, and color. Information in these signal dimensions is redundant because natural images exhibit some spatial, temporal, and chromatic regularities. Further, these signal dimensions are not independent. The incoming visual stimulus is processed and coded in the retina by spatially organized center-surround chromatically antagonistic receptive fields with complex temporal characteristics. The basic hypothesis is that the purpose of retinal signal processing is to reduce signal redundancy and to efficiently code visual information before transmission to higher stages of the visual system. Under this hypothesis it is shown that retinal coding is designed to obtain optimality in coding, considering the relative amount of information in each dimension, corresponding to a high bit rate in the spatial dimension and a low bit rate in the chromatic dimension. The coding in these dimensions achieves favorable image degradation minimizing sensitivity to picture-to-picture variations, considering the computational load required from the retina.
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Born, Werner, and Linda Schmidt. "Evaluating the Project Activity Differences in Capstone Design Students via Journals." In ASME 2018 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. American Society of Mechanical Engineers, 2018. http://dx.doi.org/10.1115/detc2018-85876.
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Teams are employed in capstone mechanical design courses, as well as in other undergraduate courses. This puts students in a setting that they will encounter as professionals, which is beneficial to their development. For instructors, however, teams make it difficult to evaluate each individual’s understanding of the design process. While specialization is not as expected in undergraduate work, the level of variation between members of a team is not fully known. In this study design journals were kept by students during their capstone projects and entries were categorized using a coding scheme. This data revealed what a typical student recorded as activity during a capstone design project. Additionally the amount of variation within a team and among students as a whole was examined.
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Lawrenson, Kate, Honglin Song, Janet Lee, Jonathan Tyrer, Susan Ramus, Paul Pharoah, and Simon Gayther. "Abstract 2559: Long non-coding RNAs as functional targets of germline genetic variation at ovarian cancer susceptibility loci." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2559.
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"Identification and variation analysis of long non-coding RNA genes expressed at early stages of seed development in Triticale." In Plant Genetics, Genomics, Bioinformatics, and Biotechnology. Novosibirsk ICG SB RAS 2021, 2021. http://dx.doi.org/10.18699/plantgen2021-043.
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Silva, Bruno S. da, and Iury da S. Batalha. "Measurement Study on 5G NSA Architecture over Fading Channel." In 11th International Conference on Signal & Image Processing (SIP 2022). Academy and Industry Research Collaboration Center (AIRCC), 2022. http://dx.doi.org/10.5121/csit.2022.121703.
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The 5G NR network with the Non-Standalone (NSA) architecture aims to advance with regard to throughput. When compared to fourth-generation mobile communication (4G LTE), the 5G has a higher data exchange capability through the gNB and the UE (User Equipment). For evaluation and optimization, it is necessary to carry out practical studies on the behaviour of the system in different environmental conditions, subject to attenuation processes, such as large-scale fading (Shading) and small-scale fading (Multipath propagation). This work has analysed the effect of the MCS (Modulation and Coding Scheme) variation on Throughput/BLER for, initially, a channel degraded by default AWGN, then the analysis extends to the multipath fading effect, which emulates more realistically a mobile communication network. The analysis confirmed the need for robust decision process algorithms in terms of MCS switching to maintain adequate data rates according to the requirement of each scenario with specific QoS (Quality of service), considering both 64 QAM and 256 QAM. The throughput degradation effect was more evident in higher-order modulations due to the higher probability of error inherent in the symbol arrangement. This study can be a key for understanding and developing huge modulation and coding schemes for fifth generation communications.
Reports on the topic "Non coding variations"
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Hanslow, Kevin. A General Welfare Decomposition for CGE Models. GTAP Technical Paper, March 2001. http://dx.doi.org/10.21642/gtap.tp19.
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Huff and Hertel (2001) derive a welfare decomposition for the equivalent variation in the GTAP model. The derivation appears to be very specific to GTAP. Nevertheless, it contains nearly all the ingredients required for performing welfare decomposition for any CGE model. In this paper, the approach of Huff and Hertel (2001) is generalised to derive a welfare decomposition that can be applied to most, if not all, CGE models. General production and utility functions are accommodated, as are foreign income flows. A brief guide to coding the proposed welfare decomposition in GEMPACK is also provided. The decomposition is applied to decomposing the equivalent variation in GTAP.
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Nelson, Gena. A Systematic Review of the Quality of Reporting in Mathematics Meta-Analyses for Students with or at Risk of Disabilities Coding Protocol. Boise State University, July 2021. http://dx.doi.org/10.18122/sped138.boisestate.
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The purpose of this document is to provide readers with the coding protocol that authors used to code 22 meta-analyses focused on mathematics interventions for students with or at-risk of disabilities. The purpose of the systematic review was to evaluate reporting quality in meta-analyses focused on mathematics interventions for students with or at risk of disabilities. To identify meta-analyses for inclusion, we considered peer-reviewed literature published between 2000 and 2020; we searched five education-focused electronic databases, scanned the table of contents of six special education journals, reviewed the curriculum vitae of researchers who frequently publish meta-analyses in mathematics and special education, and scanned the reference lists of meta-analyses that met inclusion criteria. To be included in this systematic review, meta-analyses must have reported on the effectiveness of mathematics-focused interventions, provided a summary effect for a mathematics outcome variable, and included school-aged participants with or at risk of having a disability. We identified 22 meta-analyses for inclusion. We coded each meta-analysis for 53 quality indicators (QIs) across eight categories based on recommendations from Talbott et al. (2018). Overall, the meta-analyses met 61% of QIs and results indicated that meta-analyses most frequently met QIs related to providing a clear purpose (95%) and data analysis plan (77%), whereas meta-analyses typically met fewer QIs related to describing participants (39%) and explaining the abstract screening process (48%). We discuss the variation in QI scores within and across the quality categories and provide recommendations for future researchers so that reporting in meta-analyses may be enhanced. Limitations of the current study are that grey literature was not considered for inclusion and that only meta-analyses were included; this limits the generalizability of the results to other research syntheses (e.g., narrative reviews, systematic reviews) and publication types (e.g., dissertations).
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Nelson, Gena. A Systematic Review of the Quality of Reporting in Mathematics Meta-Analyses for Students with or at Risk of Disabilities Coding Protocol. Boise State University, Albertsons Library, July 2021. http://dx.doi.org/10.18122/sped.138.boisestate.
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The purpose of this document is to provide readers with the coding protocol that authors used to code 22 meta-analyses focused on mathematics interventions for students with or at-risk of disabilities. The purpose of the systematic review was to evaluate reporting quality in meta-analyses focused on mathematics interventions for students with or at risk of disabilities. To identify meta-analyses for inclusion, we considered peer-reviewed literature published between 2000 and 2020; we searched five education-focused electronic databases, scanned the table of contents of six special education journals, reviewed the curriculum vitae of researchers who frequently publish meta-analyses in mathematics and special education, and scanned the reference lists of meta-analyses that met inclusion criteria. To be included in this systematic review, meta-analyses must have reported on the effectiveness of mathematics-focused interventions, provided a summary effect for a mathematics outcome variable, and included school-aged participants with or at risk of having a disability. We identified 22 meta-analyses for inclusion. We coded each meta-analysis for 53 quality indicators (QIs) across eight categories based on recommendations from Talbott et al. (2018). Overall, the meta-analyses met 61% of QIs and results indicated that meta-analyses most frequently met QIs related to providing a clear purpose (95%) and data analysis plan (77%), whereas meta-analyses typically met fewer QIs related to describing participants (39%) and explaining the abstract screening process (48%). We discuss the variation in QI scores within and across the quality categories and provide recommendations for future researchers so that reporting in meta-analyses may be enhanced. Limitations of the current study are that grey literature was not considered for inclusion and that only meta-analyses were included; this limits the generalizability of the results to other research syntheses (e.g., narrative reviews, systematic reviews) and publication types (e.g., dissertations).
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Ginzberg, Idit, Richard E. Veilleux, and James G. Tokuhisa. Identification and Allelic Variation of Genes Involved in the Potato Glycoalkaloid Biosynthetic Pathway. United States Department of Agriculture, August 2012. http://dx.doi.org/10.32747/2012.7593386.bard.
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Steroidal glycoalkaloids (SGAs) are secondary metabolites being part of the plant defense response. The two major SGAs in cultivated potato (Solanum tuberosum) are α-chaconine and α-solanine, which exhibit strong cellular lytic properties and inhibit acetylcholinesterase activity, and are poisonous at high concentrations for humans. As SGAs are not destroyed during cooking and frying commercial cultivars have been bred to contain low levels, and their content in tubers should not exceed 20 mg/100 g fresh weight. However, environmental factors can increase tuber SGA content above the safe level. The focus of the proposed research was to apply genomic approaches to identify candidate genes that control potato SGA content in order to develop tools for potato improvement by marker-assisted selection and/or transgenic approaches. To this end, the objectives of the proposal included identification of genes, metabolic intermediates and allelic variations in the potato SGAbiosynthetic pathway. The SGAs are biosynthesized by the sterol branch of the mevalonic acid/isoprenoid pathway. Transgenic potato plants that overexpress 3-hydroxy-3-methylglutaryl-CoA reductase 1 (HMG1) or squalene synthase 1 (SQS1), key enzymes of the mevalonic acid/isoprenoid pathway, exhibited elevated levels of solanine and chaconine as well as induced expression of genes downstream the pathway. These results suggest of coordinated regulation of isoprenoid (primary) metabolism and SGA secondary metabolism. The transgenic plants were further used to identify new SGA-related candidate genes by cDNA-AFLP approach and a novel glycosyltransferase was isolated. In addition, genes involved in phytosterol biosynthesis may have dual role and synthesize defense-related steroidal metabolites, such as SGAs, via lanosterol pathway. Potato lanosterol synthase sequence (LAS) was isolated and used to prepare transgenic plants with overexpressing and silencing constructs. Plants are currently being analyzed for SGA content. The dynamics of SGA accumulation in the various organs of a potato species with high SGA content gave insights into the general regulation of SGA abundance. Leaf SGA levels in S. chacoense were 10 to 20-fold greater than those of S. tuberosum. The leptines, SGAs with strong antifeedant properties against Colorado potato beetles, were present in all aerial tissues except for early and mid-developmental stages of above ground stolons, and accounted for the high SGA content of S. chacoense. These results indicate the presence of regulatory mechanisms in most tissues except in stolons that limit the levels of α-solanine and α-chaconine and confine leptine accumulation to the aerial tissues. The genomes of cultivated and wild potato contain a 4-member gene family coding for SQS. Three orthologs were cloned as cDNAs from S. chacoense and heterologously expressed in E. coli. Squalene accumulated in all E. coli lines transformed with each of the three gene constructs. Differential transcript abundance in various organs and amino acid sequence differences in the conserved domains of three isoenzymes indicate subfunctionalization of SQS activity and triterpene/sterol metabolism. Because S. chacoense and S. phureja differ so greatly for presence and accumulation of SGAs, we selected four candidate genes from different points along the biosynthetic pathway to determine if chcor phuspecific alleles were associated with SGA expression in a segregating interspecific diploid population. For two of the four genes (HMG2 and SGT2) F2 plants with chcalleles expressed significantly greater total SGAs compared with heterozygotes and those with phualleles. Although there are other determinants of SGA biosynthesis and composition in potato, the ability of allelic states at two genes to affect SGA levels confirms some of the above transgenic work where chcalleles at two other loci altered SGA expression in Desiree. Present results reveal new opportunities to manipulate triterpene/sterol biosynthesis in more targeted ways with the objective of altering SGA content for both human health concerns and natural pesticide content without disrupting the essential metabolism and function of the phytosterol component of the membranes and the growth regulating brassinosteroids.
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Cohen, Deborah J., Annette M. Totten, Robert L. Phillips, Jr., Yalda Jabbarpour, Anuradha Jetty, Jennifer DeVoe, Miranda Pappas, Jordan Byers, and Erica Hart. Measuring Primary Healthcare Spending. Agency for Healthcare Research and Quality (AHRQ), May 2024. http://dx.doi.org/10.23970/ahrqepctb44.
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Background. Policy leaders and researchers have identified a range of primary care spending conceptualizations, developed frameworks and methods for measuring primary care spending, and documented the pros and cons of different approaches. However, these efforts have not been comprehensive, particularly as the number of estimates has grown. We continue this work by identifying the definitions, data sources, and approaches used to estimate primary care spending in the United States. Our objective was to identify where there is and is not consensus across methods, and how initial steps toward a standardized approach to estimating primary care spending might be achieved. We approached this comparison from a societal economic perspective. Methods. Searches were conducted in Ovid MEDLINE® and Cochrane CENTRAL databases (inception to May 2, 2023), and were supplemented by manual reviews of reference lists, Scopus searches of key articles, gray literature searches of State and organization websites, and responses to a Federal Register Notice, as well as recommendations from Key Informants. Websites of States and organizations that produced reports were reviewed in November 2023 to identify updates. Publicly available estimates and reports of methods were supplemented by discussions with experts who have supported States’ estimates. Findings. We identified 67 primary care spending estimates for 2010 to 2021: 42 of these were produced by 11 State Governments for their State, 2 were published by the Veterans Health Administration, and 23 were published by researchers or other organizations, which include foundations and policy organizations. Forty-four estimates reported on primary care spending for a single State, one estimate reported spending for the New England States, and 22 reported national spending. To date, 13 State Governments have developed and/or are implementing measurements of primary care spending. When State Governments measure primary care spending, they produce regular, often yearly, estimates. States have produced one to eight estimates, demonstrating some States have more experience with this task than others. Primary care spending estimates in our sample ranged from 3.1 to 10.3 percent. These estimates started with definitions of primary care, which are often labeled narrow or broad. Estimates may use these same labels to mean different things. Narrow definitions of primary care usually include fewer providers, locations, or service types, while broad definitions include more. State, regional, or national estimates are either reported as two estimates, one using a narrow and one using a broad definition of primary care, or as a single estimate labeled neither narrow nor broad. Variations in what providers, services, and locations are included in definitions of primary care are significant and likely contribute to variation in primary care spending estimates. However, it is difficult to distinguish differences in definitions and measurement from differences in actual primary care spending. Conclusions. While there are some core similarities in how primary care spending is measured across State, regional, and national estimates, there are more differences. While there may be rationale behind some of these variations, this variation limits comparisons and what could be understood about the impact of policies. Furthermore, lack of clear, detailed reporting of methods can obscure precisely how and why estimates differ. Research is needed that quantifies the impact different decisions and measurement methods have on spending estimates. To assure the validity and reliability of estimates of primary care spending, and facilitate comparisons and links to health outcomes, Federal, State, and policy leaders need to: (1) collaborate to create a primary care clinician database that can function as a public utility for States to allow for more precise identification of primary care clinics and clinicians, and reduce reliance on Current Procedural Terminology/Healthcare Common Procedure Coding System codes; (2) develop a template for transparent reporting of methods used to estimate primary care spending; (3) foster collaboration among Federal agencies and State leaders to develop a consensus definition of primary care and process for estimating primary care spending, with consideration of methods that are easy to understand and transparent; and (4) support the development and ongoing maintenance of State All-Payer Claims Databases, expand to include nonclaims payments, and supply Medicare and Medicaid estimates for every State.
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Bennett, Alan B., Arthur A. Schaffer, Ilan Levin, Marina Petreikov, and Adi Doron-Faigenboim. Manipulating fruit chloroplasts as a strategy to improve fruit quality. United States Department of Agriculture, January 2013. http://dx.doi.org/10.32747/2013.7598148.bard.
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The Original Objectives were modified and two were eliminated to reflect the experimental results: Objective 1 - Identify additional genetic variability in SlGLK2 and IPin wild, traditional and heirloom tomato varieties Objective 2 - Determine carbon balance and horticultural characteristics of isogenic lines expressing functional and non-functional alleles of GLKsand IP Background: The goal of the research was to understand the unique aspects of chloroplasts and photosynthesis in green fruit and the consequences of increasing the chloroplast capacity of green fruit for ripe fruit sugars, yield, flavor and nutrient qualities. By focusing on the regulation of chloroplast formation and development solely in fruit, our integrated knowledge of photosynthetic structures/organs could be broadened and the results of the work could impact the design of manipulations to optimize quality outputs for the agricultural fruit with enhanced sugars, nutrients and flavors. The project was based on the hypothesis that photosynthetic and non-photosynthetic plastid metabolism in green tomato fruit is controlled at a basal level by light for minimal energy requirements but fruit-specific genes regulate further development of robust chloroplasts in this organ. Our BARD project goals were to characterize and quantitate the photosynthesis and chloroplast derived products impacted by expression of a tomato Golden 2- like 2 transcription factor (US activities) in a diverse set of 31 heirloom tomato lines and examine the role of another potential regulator, the product of the Intense Pigment gene (IP activities). Using tomato Golden 2-like 2 and Intense Pigment, which was an undefined locus that leads to enhanced chloroplast development in green fruit, we sought to determine the benefits and costs of extensive chloroplast development in fruit prior to ripening. Major conclusions, solutions, achievements: Single nucleotide polymorphisms in the promoter, coding and intronicSlGLK2 sequences of 20 heirloom tomato lines were identified and three SlGLK2 promoter lineages were identified; two lineages also had striped fruit variants. Lines with striped fruit but no shoulders were not identified. Green fruit chlorophyll and ripe fruit soluble sugar levels were measured in 31 heirloom varieties and fruit size correlates with ripe fruit sugars but dark shoulders does not. A combination of fine mapping, recombinant generation, RNAseq expression and SNP calling all indicated that the proposed localization of a single locus IP on chr 10 was incorrect. Rather, the IP line harbored 11 separate introgressions from the S. chmielewskiparent, scattered throughout the genome. These introgressions harbored ~3% of the wild species genome and no recombinant consistently recovered the IP parental phenotype. The 11 introgressions were dissected into small combinations in segregating recombinant populations. Based on these analyses two QTL for Brix content were identified, accounting for the effect of increased Brix in the IP line. Scientific and agricultural implications: SlGLK2 sequence variation in heirloom tomato varieties has been identified and can be used to breed for differences in SlGLK2 expression and possibly in the green striped fruit phenotype. Two QTL for Brix content have been identified in the S. chmielewskiparental line and these can be used for increasing soluble solids contents in breeding programs.