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https://www.readbyqxmd.com/read/28938601/mutation-profile-based-methods-for-understanding-selection-forces-in-cancer-somatic-mutations-a-comparative-analysis
#1
Zhan Zhou, Yangyun Zou, Gangbiao Liu, Jingqi Zhou, Jingcheng Wu, Shimin Zhao, Zhixi Su, Xun Gu
Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes (CN /CS ) and normal populations (pN /pS ). A new mutation-profile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28934386/expression-of-the-neuropathy-associated-mtmr2-gene-rescues-mtm1-associated-myopathy
#2
Matthieu A Raess, Belinda S Cowling, Dimitri L Bertazzi, Christine Kretz, Bruno Rinaldi, Jean-Marie Xuereb, Pascal Kessler, Norma B Romero, Bernard Payrastre, Sylvie Friant, Jocelyn Laporte
Myotubularins (MTMs) are active or dead phosphoinositides phosphatases defining a large protein family conserved through evolution and implicated in different neuromuscular diseases. Loss-of-function mutations in MTM1 cause the severe congenital myopathy called myotubular myopathy (or X-linked centronuclear myopathy) while mutations in the MTM1-related protein MTMR2 cause a recessive Charcot-Marie-Tooth peripheral neuropathy. Here we aimed to determine the functional specificity and redundancy of MTM1 and MTMR2, and to assess their abilities to compensate for a potential therapeutic strategy...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28931559/variation-in-position-effect-variegation-within-a-natural-population
#3
Keegan J P Kelsey, Andrew G Clark
Changes in chromatin state may drive changes in gene expression, and it is of growing interest to understand the population genetic forces that drive differences in chromatin state. Here, we use the phenomenon of position effect variegation (PEV), a well-studied proxy for chromatin state, to survey variation in PEV among a naturally derived population. Further, we explore the genetic architecture of natural variation in factors that modify PEV. While previous mutation screens have identified over 150 suppressors and enhancers of PEV, it remains unknown to what extent allelic variation in these modifiers mediate inter-individual variation in PEV...
September 20, 2017: Genetics
https://www.readbyqxmd.com/read/28922870/male-mutation-bias-is-the-main-force-shaping-chromosomal-substitution-rates-in-monotreme-mammals
#4
Vivian Link, Diana Aguilar-Gómez, Ciro Ramírez-Suástegui, Laurence D Hurst, Diego Cortez
In many species, spermatogenesis involves more cell divisions than oogenesis, and the male germline, therefore, accumulates more DNA replication errors, a phenomenon known as male mutation bias. The extent of male mutation bias (α) is estimated by comparing substitution rates of the X, Y, and autosomal chromosomes, as these chromosomes spend different proportions of their time in the germlines of the two sexes. Male mutation bias has been characterized in placental and marsupial mammals as well as birds, but analyses in monotremes failed to detect any such bias...
September 1, 2017: Genome Biology and Evolution
https://www.readbyqxmd.com/read/28921675/altered-cav1-2-function-in-the-timothy-syndrome-mouse-model-produces-ascending-serotonergic-abnormalities
#5
Daniel G Ehlinger, Kathryn G Commons
Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder, and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy Syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders, we investigate the relationship between Cav1...
September 16, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28886708/cancer-heterogeneity-converting-a-limitation-into-a-source-of-biologic-information
#6
REVIEW
Albert Rübben, Arturo Araujo
Analysis of spatial and temporal genetic heterogeneity in human cancers has revealed that somatic cancer evolution in most cancers is not a simple linear process composed of a few sequential steps of mutation acquisitions and clonal expansions. Parallel evolution has been observed in many early human cancers resulting in genetic heterogeneity as well as multilineage progression. Moreover, aneuploidy as well as structural chromosomal aberrations seems to be acquired in a non-linear, punctuated mode where most aberrations occur at early stages of somatic cancer evolution...
September 8, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28885715/genome-evolution-is-driven-by-gene-expression-generated-biophysical-constraints-through-rna-directed-genetic-variation-a-hypothesis
#7
REVIEW
Didier Auboeuf
The biogenesis of RNAs and proteins is a threat to the cell. Indeed, the act of transcription and nascent RNAs challenge DNA stability. Both RNAs and nascent proteins can also initiate the formation of toxic aggregates because of their physicochemical properties. In reviewing the literature, I show that co-transcriptional and co-translational biophysical constraints can trigger DNA instability that in turn increases the likelihood that sequences that alleviate the constraints emerge over evolutionary time. These directed genetic variations rely on the biogenesis of small RNAs that are transcribed directly from challenged DNA regions or processed from the transcripts that directly or indirectly generate constraints or aggregates...
September 8, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28884772/afm-combined-to-atr-ftir-reveals-candida-cell-wall-changes-under-caspofungin-treatment
#8
Fabienne Quilès, Isabelle Accoceberry, Célia Couzigou, Grégory Francius, Thierry Noël, Sofiane El-Kirat-Chatel
Fungal pathogens from Candida genus are responsible for severe life-threatening infections and the antifungal arsenal is still limited. Caspofungin, an antifungal drug used for human therapy, acts as a blocking agent of the cell wall synthesis by inhibiting the β-1,3-glucan-synthase encoded by FKS genes. Despite its efficiency, the number of genetic mutants that are resistant to caspofungin is increasing. An important challenge to improve antifungal therapy is to understand cellular phenomenon that are associated with drug resistance...
September 21, 2017: Nanoscale
https://www.readbyqxmd.com/read/28880857/brca-genetic-testing-and-receipt-of-preventive-interventions-among-women-aged-18-64-years-with-employer-sponsored-health-insurance-in-nonmetropolitan-and-metropolitan-areas-united-states-2009-2014
#9
Katherine Kolor, Zhuo Chen, Scott D Grosse, Juan L Rodriguez, Ridgely Fisk Green, W David Dotson, M Scott Bowen, Julie A Lynch, Muin J Khoury
PROBLEM/CONDITION: Genetic testing for breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) gene mutations can identify women at increased risk for breast and ovarian cancer. These testing results can be used to select preventive interventions and guide treatment. Differences between nonmetropolitan and metropolitan populations in rates of BRCA testing and receipt of preventive interventions after testing have not previously been examined. PERIOD COVERED: 2009-2014...
September 8, 2017: MMWR. Surveillance Summaries: Morbidity and Mortality Weekly Report. Surveillance Summaries
https://www.readbyqxmd.com/read/28878013/new-class-of-precision-antimicrobials-redefines-role-of-clostridium-difficile-s-layer-in-virulence-and-viability
#10
Joseph A Kirk, Dana Gebhart, Anthony M Buckley, Stephen Lok, Dean Scholl, Gillian R Douce, Gregory R Govoni, Robert P Fagan
There is a medical need for antibacterial agents that do not damage the resident gut microbiota or promote the spread of antibiotic resistance. We recently described a prototypic precision bactericidal agent, Av-CD291.2, which selectively kills specific Clostridium difficile strains and prevents them from colonizing mice. We have since selected two Av-CD291.2-resistant mutants that have a surface (S)-layer-null phenotype due to distinct point mutations in the slpA gene. Using newly identified bacteriophage receptor binding proteins for targeting, we constructed a panel of Avidocin-CDs that kills diverse C...
September 6, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28869687/ancestral-acquisitions-gene-flow-and-multiple-evolutionary-trajectories-of-the-type-three-secretion-system-and-effectors-in-xanthomonas-plant-pathogens
#11
Déborah Merda, Martial Briand, Eran Bosis, Céline Rousseau, Perrine Portier, Matthieu Barret, Marie-Agnès Jacques, Marion Fischer-Le Saux
Deciphering the evolutionary history and transmission patterns of virulence determinants is necessary to understand the emergence of novel pathogens. The main virulence determinant of most pathogenic proteobacteria is the type three secretion system (T3SS). The Xanthomonas genus includes bacteria responsible for numerous epidemics in agroecosystems worldwide and represents a major threat to plant health. The main virulence factor of Xanthomonas is the Hrp2 family T3SS, however this system is not conserved in all strains and it has not been previously determined whether the distribution of T3SS in this bacterial genus has resulted from losses or independent acquisitions...
September 4, 2017: Molecular Ecology
https://www.readbyqxmd.com/read/28866311/filaggrin-mutations-and-molluscum-contagiosum-skin-infection-in-patients-with-atopic-dermatitis
#12
Sara Manti, Maria Amorini, Caterina Cuppari, Annamaria Salpietro, Francesca Porcino, Salvatore Leonardi, Michele Miraglia Del Giudice, Gianluigi Marseglia, Davide Paolo Caimmi, Carmelo Salpietro
BACKGROUND: Although mutations in the filaggrin (FLG) gene have been reported to predispose patients with atopic dermatitis (AD) skin infection susceptibility, to date, the data reported in the literature are still controversial. OBJECTIVE: To evaluate the role of FLG polymorphisms expression and risk of developing a concomitant Molluscum contagiosum sustained skin infection in the pediatric population with AD. METHODS: A total of 100 children with AD and 97 healthy children were enrolled...
August 30, 2017: Annals of Allergy, Asthma & Immunology
https://www.readbyqxmd.com/read/28855255/single-molecule-force-spectroscopy-on-histone-h4-tail-cross-linked-chromatin-reveals-fiber-folding
#13
Artur Kaczmarczyk, Abdollah Allahverdi, Thomas B Brouwer, Lars Nordenskiöld, Nynke H Dekker, John van Noort
The eukaryotic genome is highly compacted into a protein-DNA complex called chromatin. The cell controls access of transcriptional regulators to chromosomal DNA via several mechanisms that act on chromatin-associated proteins and provide a rich spectrum of epigenetic regulation. Elucidating the mechanisms that fold chromatin fibers into higher-order structures is therefore key to understanding the epigenetic regulation of DNA accessibility. Here, using histone H4-V21C and histone H2A-E64C mutations, we employed single-molecule force spectroscopy to measure the unfolding of individual chromatin fibers that are reversibly cross-linked through the histone H4 tail...
August 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28852935/shp2-regulates-proliferation-and-tumorigenicity-of-glioma-stem-cells
#14
Laura Roccograndi, Zev A Binder, Logan Zhang, Nicola Aceto, Zhuo Zhang, Mohamed Bentires-Alj, Ichiro Nakano, Nadia Dahmane, Donald M O'Rourke
SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM. Given the importance of SHP2 in developing neural stem cells, and the importance of glioma stem cells (GSCs) in GBM oncogenesis, we explored the functional role of SHP2 in GSCs...
August 29, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28827114/factors-affecting-the-codon-usage-bias-of-sry-gene-across-mammals
#15
Supriyo Chakraborty, Arif Uddin, Monisha Nath Choudhury
Codon usage bias (CUB) is extensively found in a wide variety genomes and it is mostly affected by mutation pressure and natural selection. Analysis of CUB helps in studying the evolutionary features of a genome. The SRY gene plays an important role in male reproductive organ and a good candidate to study the evolutionary forces, since little work was reported earlier on this gene. We used bioinformatic methods to analyze the protein-coding sequences of SRY gene in 172 different mammalian species to understand the patterns of codon usage and the evolutionary forces acting on it...
September 30, 2017: Gene
https://www.readbyqxmd.com/read/28821864/nanomechanics-of-multidomain-neuronal-cell-adhesion-protein-contactin-revealed-by-single-molecule-afm-and-smd
#16
K Mikulska-Ruminska, A J Kulik, C Benadiba, I Bahar, G Dietler, W Nowak
Contactin-4 (CNTN4) is a complex cell adhesion molecule (CAM) localized at neuronal membranes, playing a key role in maintaining the mechanical integrity and signaling properties of the synapse. CNTN4 consists of six immunoglobulin C2 type (IgC2) domains and four fibronectin type III (FnIII) domains that are shared with many other CAMs. Mutations in CNTN4 gene have been linked to various psychiatric disorders. Toward elucidating the response of this modular protein to mechanical stress, we studied its force-induced unfolding using single molecule atomic force microscopy (smAFM) and steered molecular dynamics (SMD) simulations...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821587/drift-induced-selection-between-male-and-female-heterogamety
#17
Carl Veller, Pavitra Muralidhar, George W A Constable, Martin A Nowak
Evolutionary transitions between male and female heterogamety are common in both vertebrates and invertebrates. Theoretical studies of these transitions have found that, when all genotypes are equally fit, continuous paths of intermediate equilibria link the two sex chromosome systems. This observation has led to a belief that neutral evolution along these paths can drive transitions, and that arbitrarily small fitness differences among sex chromosome genotypes can determine the system to which evolution leads...
August 16, 2017: Genetics
https://www.readbyqxmd.com/read/28815464/inherited-nonsyndromic-ichthyoses-an-update-on-pathophysiology-diagnosis-and-treatment
#18
REVIEW
Anders Vahlquist, Judith Fischer, Hans Törmä
Hereditary ichthyoses are due to mutations on one or both alleles of more than 30 different genes, mainly expressed in the upper epidermis. Syndromic as well as nonsyndromic forms of ichthyosis exist. Irrespective of etiology, virtually all types of ichthyosis exhibit a defective epidermal barrier that constitutes the driving force for hyperkeratosis, skin scaling, and inflammation. In nonsyndromic forms, these features are most evident in severe autosomal recessive congenital ichthyosis (ARCI) and epidermolytic ichthyosis, but to some extent also occur in the common type of non-congenital ichthyosis...
August 16, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28797108/natural-disease-history-of-mouse-models-for-limb-girdle-muscular-dystrophy-types-2d-and-2f
#19
S Pasteuning-Vuhman, K Putker, C L Tanganyika-de Winter, J W Boertje-van der Meulen, L van Vliet, M Overzier, J J Plomp, A Aartsma-Rus, M van Putten
Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models...
2017: PloS One
https://www.readbyqxmd.com/read/28793217/mutation-in-the-core-structure-of-desmin-intermediate-filaments-affects-myoblast-elasticity
#20
Catherine Even, Gilles Abramovici, Florence Delort, Anna F Rigato, Virginie Bailleux, Abel de Sousa Moreira, Patrick Vicart, Felix Rico, Sabrina Batonnet-Pichon, Fatma Briki
Elastic properties of cells are mainly derived from the actin cytoskeleton. However, intermediate filaments are emerging as major contributors to the mechanical properties of cells. Using atomic force microscopy, we studied the elasticity of mouse myoblasts expressing a mutant form of the gene encoding for desmin intermediate filaments, p.D399Y. This variant produces desmin aggregates, the main pathological symptom of myofibrillar myopathies. Here we show that desmin-mutated cells display a 39% increased median elastic modulus compared to wild-type cells...
August 8, 2017: Biophysical Journal
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