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https://www.readbyqxmd.com/read/29681884/glutathione-s-transferase-alpha-4-prevents-dopamine-neurodegeneration-in-a-rat-alpha-synuclein-model-of-parkinson-s-disease
#1
Michael Jewett, Elna Dickson, Kajsa Brolin, Matilde Negrini, Itzia Jimenez-Ferrer, Maria Swanberg
Parkinson's disease (PD) is a common, progressive neurodegenerative disease, which typically presents itself with a range of motor symptoms, like resting tremor, bradykinesia, and rigidity, but also non-motor symptoms such as fatigue, constipation, and sleep disturbance. Neuropathologically, PD is characterized by loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) and Lewy bodies, neuronal inclusions containing α-synuclein (α-syn). Mutations and copy number variations of SNCA , the gene encoding α-syn, are linked to familial PD and common SNCA gene variants are associated to idiopathic PD...
2018: Frontiers in Neurology
https://www.readbyqxmd.com/read/29681821/genomic-profiling-of-two-histologically-distinct-rare-urothelial-cancers-in-a-clinical-setting-to-identify-potential-therapeutic-options-for-treatment-and-management-of-disease
#2
Andrew N Hesse, William Fabricius, Christian A Thomas, Ramesh Gaindh, Robert Christman, Pavalan Selvam, Matthew Prego, Gregory Lewis, Jasmina Uvalic, Daniel Bergeron, Shelbi Burns, Bridgette Sisson, Kevin Kelly, Jens Rueter, Honey V Reddi
Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors...
January 2018: Case Reports in Oncology
https://www.readbyqxmd.com/read/29675612/complement-receptor-1-gene-cr1-intragenic-duplication-and-risk-of-alzheimer-s-disease
#3
Ezgi Kucukkilic, Keeley Brookes, Imelda Barber, Tamar Guetta-Baranes, Kevin Morgan, Edward J Hollox
Single nucleotide variants (SNVs) within and surrounding the complement receptor 1 (CR1) gene show some of the strongest genome-wide association signals with late-onset Alzheimer's disease. Some studies have suggested that this association signal is due to a duplication allele (CR1-B) of a low copy repeat (LCR) within the CR1 gene, which increases the number of complement C3b/C4b-binding sites in the mature receptor. In this study, we develop a triplex paralogue ratio test assay for CR1 LCR copy number allowing large numbers of samples to be typed with a limited amount of DNA...
April 19, 2018: Human Genetics
https://www.readbyqxmd.com/read/29669917/ribosomal-dna-copy-loss-and-repeat-instability-in-atrx-mutated-cancers
#4
Maheshi Udugama, Elaine Sanij, Hsiao P J Voon, Jinbae Son, Linda Hii, Jeremy D Henson, F Lyn Chan, Fiona T M Chang, Yumei Liu, Richard B Pearson, Paul Kalitsis, Jeffrey R Mann, Philippe Collas, Ross D Hannan, Lee H Wong
ATRX (alpha thalassemia/mental retardation X-linked) complexes with DAXX to deposit histone variant H3.3 into repetitive heterochromatin. Recent genome sequencing studies in cancers have revealed mutations in ATRX and their association with ALT (alternative lengthening of telomeres) activation. Here we report depletion of ATRX in mouse ES cells leads to selective loss in ribosomal RNA gene (rDNA) copy number. Supporting this, ATRX-mutated human ALT-positive tumors also show a substantially lower rDNA copy than ALT-negative tumors...
April 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29665859/morphology-and-genomic-hallmarks-of-breast-tumours-developed-by-atm-deleterious-variant-carriers
#5
Anne-Laure Renault, Noura Mebirouk, Laetitia Fuhrmann, Guillaume Bataillon, Eve Cavaciuti, Dorothée Le Gal, Elodie Girard, Tatiana Popova, Philippe La Rosa, Juana Beauvallet, Séverine Eon-Marchais, Marie-Gabrielle Dondon, Catherine Dubois d'Enghien, Anthony Laugé, Walid Chemlali, Virginie Raynal, Martine Labbé, Ivan Bièche, Sylvain Baulande, Jacques-Olivier Bay, Pascaline Berthet, Olivier Caron, Bruno Buecher, Laurence Faivre, Marc Fresnay, Marion Gauthier-Villars, Paul Gesta, Nicolas Janin, Sophie Lejeune, Christine Maugard, Sébastien Moutton, Laurence Venat-Bouvet, Hélène Zattara, Jean-Pierre Fricker, Laurence Gladieff, Isabelle Coupier, Georgia Chenevix-Trench, Janet Hall, Anne Vincent-Salomon, Dominique Stoppa-Lyonnet, Nadine Andrieu, Fabienne Lesueur
BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is a moderate-risk breast cancer susceptibility gene; germline loss-of-function variants are found in up to 3% of hereditary breast and ovarian cancer (HBOC) families who undergo genetic testing. So far, no clear histopathological and molecular features of breast tumours occurring in ATM deleterious variant carriers have been described, but identification of an ATM-associated tumour signature may help in patient management. METHODS: To characterise hallmarks of ATM-associated tumours, we performed systematic pathology review of tumours from 21 participants from ataxia-telangiectasia families and 18 participants from HBOC families, as well as copy number profiling on a subset of 23 tumours...
April 17, 2018: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29658776/toward-recovering-allele-specific-cancer-genome-graphs
#6
Ashok Rajaraman, Jian Ma
Integrated analysis of structural variants (SVs) and copy number alterations in aneuploid cancer genomes is key to understanding tumor genome complexity. A recently developed algorithm, Weaver, can estimate, for the first time, allele-specific copy number of SVs and their interconnectivity in aneuploid cancer genomes. However, one major limitation is that not all SVs identified by Weaver are phased. In this article, we develop a general convex programming framework that predicts the interconnectivity of unphased SVs with possibly noisy allele-specific copy number estimations as input...
April 16, 2018: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
https://www.readbyqxmd.com/read/29656860/truncating-variants-in-naa15-are-associated-with-variable-levels-of-intellectual-disability-autism-spectrum-disorder-and-congenital-anomalies
#7
Hanyin Cheng, Avinash V Dharmadhikari, Sylvia Varland, Ning Ma, Deepti Domingo, Robert Kleyner, Alan F Rope, Margaret Yoon, Asbjørg Stray-Pedersen, Jennifer E Posey, Sarah R Crews, Mohammad K Eldomery, Zeynep Coban Akdemir, Andrea M Lewis, Vernon R Sutton, Jill A Rosenfeld, Erin Conboy, Katherine Agre, Fan Xia, Magdalena Walkiewicz, Mauro Longoni, Frances A High, Marjon A van Slegtenhorst, Grazia M S Mancini, Candice R Finnila, Arie van Haeringen, Nicolette den Hollander, Claudia Ruivenkamp, Sakkubai Naidu, Sonal Mahida, Elizabeth E Palmer, Lucinda Murray, Derek Lim, Parul Jayakar, Michael J Parker, Stefania Giusto, Emanuela Stracuzzi, Corrado Romano, Jennifer S Beighley, Raphael A Bernier, Sébastien Küry, Mathilde Nizon, Mark A Corbett, Marie Shaw, Alison Gardner, Christopher Barnett, Ruth Armstrong, Karin S Kassahn, Anke Van Dijck, Geert Vandeweyer, Tjitske Kleefstra, Jolanda Schieving, Marjolijn J Jongmans, Bert B A de Vries, Rolph Pfundt, Bronwyn Kerr, Samantha K Rojas, Kym M Boycott, Richard Person, Rebecca Willaert, Evan E Eichler, R Frank Kooy, Yaping Yang, Joseph C Wu, James R Lupski, Thomas Arnesen, Gregory M Cooper, Wendy K Chung, Jozef Gecz, Holly A F Stessman, Linyan Meng, Gholson J Lyon
N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15...
April 9, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29656859/dual-molecular-effects-of-dominant-rora-mutations-cause-two-variants-of-syndromic-intellectual-disability-with-either-autism-or-cerebellar-ataxia
#8
Claire Guissart, Xenia Latypova, Paul Rollier, Tahir N Khan, Hannah Stamberger, Kirsty McWalter, Megan T Cho, Susanne Kjaergaard, Sarah Weckhuysen, Gaetan Lesca, Thomas Besnard, Katrin Õunap, Lynn Schema, Andreas G Chiocchetti, Marie McDonald, Julitta de Bellescize, Marie Vincent, Hilde Van Esch, Shannon Sattler, Irman Forghani, Isabelle Thiffault, Christine M Freitag, Deborah Sara Barbouth, Maxime Cadieux-Dion, Rebecca Willaert, Maria J Guillen Sacoto, Nicole P Safina, Christèle Dubourg, Lauren Grote, Wilfrid Carré, Carol Saunders, Sander Pajusalu, Emily Farrow, Anne Boland, Danielle Hays Karlowicz, Jean-François Deleuze, Monica H Wojcik, Rena Pressman, Bertrand Isidor, Annick Vogels, Wim Van Paesschen, Lihadh Al-Gazali, Aisha Mohamed Al Shamsi, Mireille Claustres, Aurora Pujol, Stephan J Sanders, François Rivier, Nicolas Leboucq, Benjamin Cogné, Souphatta Sasorith, Damien Sanlaville, Kyle Retterer, Sylvie Odent, Nicholas Katsanis, Stéphane Bézieau, Michel Koenig, Erica E Davis, Laurent Pasquier, Sébastien Küry
RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy...
April 10, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29656515/comparative-cyp-omic-analysis-between-the-ddt-susceptible-and-resistant-drosophila-melanogaster-strains-91-c-and-91-r
#9
Keon Mook Seong, Brad S Coates, May R Berenbaum, John M Clark, Barry R Pittendrigh
BACKGROUND: Cytochrome P450 monooxygenases (P450s) are involved in the biosynthesis of endogenous intracellular compounds and the metabolism of xenobiotics, including chemical insecticides. We investigated the structural and expression level variance across all P450 genes with respect to the evolution of insecticide resistance under multigenerational DDT selection. RESULTS: RNA-seq and reverse transcriptase quantitative PCR indicated that the transcript levels of seven P450 genes were significantly up-regulated and three P450 genes were down-regulated in the DDT-resistant strain 91-R, as compared to the control strain 91-C...
April 15, 2018: Pest Management Science
https://www.readbyqxmd.com/read/29655801/analysis-of-intragenic-ush2a-copy-number-variation-unveils-broad-spectrum-of-unique-and-recurrent-variants
#10
Christina A Austin-Tse, Diana L Mandelker, Andrea M Oza, Heather Mason-Suares, Heidi L Rehm, Sami S Amr
Given that all forms of Usher syndrome (USH) present with hearing loss in advance of retinal disease, the syndromic nature of the disorder is rarely appreciated when critical management decisions are being made. As a result, molecular diagnostics are crucial in guiding the management of USH patients. While 11 genes have been associated with USH, the USH2A gene is one of the largest contributors. Approximately 20% of suspected USH probands that undergo USH2A sequencing at our laboratory receive an inconclusive result due to the identification of a monoallelic disease-causing variant in USH2A...
April 12, 2018: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29650813/-the-cutting-edge-of-sarcoma-genomics
#11
Katsuhito Takahashi
Sarcoma is well-known rare cancer with few therapeutic options. Recent comprehensive genomic analyses of adult soft tissue sarcoma revealed few somatic mutations and massive copy number variations(CNVs)by the specific chromosomes. Those features are quite different from the genomics of carcinoma such as lung and colon cancers in which driver and passenger mutations play a central role in the pathogenesis. Furthermore, it has been demonstrated that substantial population of sarcoma patients has pathological germline variants of cancer predisposition genes...
April 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/29649263/validation-of-czecanca-czech-cancer-panel-for-clinical-application-for-targeted-ngs-based-analysis-of-hereditary-cancer-syndromes
#12
Jana Soukupova, Petra Zemankova, Klara Lhotova, Marketa Janatova, Marianna Borecka, Lenka Stolarova, Filip Lhota, Lenka Foretova, Eva Machackova, Viktor Stranecky, Spiros Tavandzis, Petra Kleiblova, Michal Vocka, Hana Hartmannova, Katerina Hodanova, Stanislav Kmoch, Zdenek Kleibl
BACKGROUND: Carriers of mutations in hereditary cancer predisposition genes represent a small but clinically important subgroup of oncology patients. The identification of causal germline mutations determines follow-up management, treatment options and genetic counselling in patients' families. Targeted next-generation sequencing-based analyses using cancer-specific panels in high-risk individuals have been rapidly adopted by diagnostic laboratories. While the use of diagnosis-specific panels is straightforward in typical cases, individuals with unusual phenotypes from families with overlapping criteria require multiple panel testing...
2018: PloS One
https://www.readbyqxmd.com/read/29649218/global-characterization-of-copy-number-variants-in-epilepsy-patients-from-whole-genome-sequencing
#13
Jean Monlong, Simon L Girard, Caroline Meloche, Maxime Cadieux-Dion, Danielle M Andrade, Ron G Lafreniere, Micheline Gravel, Dan Spiegelman, Alexandre Dionne-Laporte, Cyrus Boelman, Fadi F Hamdan, Jacques L Michaud, Guy Rouleau, Berge A Minassian, Guillaume Bourque, Patrick Cossette
Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs...
April 12, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29643504/genome-evolution-across-1-011-saccharomyces-cerevisiae-isolates
#14
Jackson Peter, Matteo De Chiara, Anne Friedrich, Jia-Xing Yue, David Pflieger, Anders Bergström, Anastasie Sigwalt, Benjamin Barre, Kelle Freel, Agnès Llored, Corinne Cruaud, Karine Labadie, Jean-Marc Aury, Benjamin Istace, Kevin Lebrigand, Pascal Barbry, Stefan Engelen, Arnaud Lemainque, Patrick Wincker, Gianni Liti, Joseph Schacherer
Large-scale population genomic surveys are essential to explore the phenotypic diversity of natural populations. Here we report the whole-genome sequencing and phenotyping of 1,011 Saccharomyces cerevisiae isolates, which together provide an accurate evolutionary picture of the genomic variants that shape the species-wide phenotypic landscape of this yeast. Genomic analyses support a single 'out-of-China' origin for this species, followed by several independent domestication events. Although domesticated isolates exhibit high variation in ploidy, aneuploidy and genome content, genome evolution in wild isolates is mainly driven by the accumulation of single nucleotide polymorphisms...
April 11, 2018: Nature
https://www.readbyqxmd.com/read/29629500/altered-structural-brain-connectivity-involving-the-dorsal-and-ventral-language-pathways-in-16p11-2-deletion-syndrome
#15
Banu Ahtam, Naira Link, Erikson Hoff, P Ellen Grant, Kiho Im
Copy number variants at the chromosomal locus 16p11.2 contribute to neurodevelopmental disorders such as autism spectrum disorders, epilepsy, schizophrenia, and language and articulation disorders. Here, we provide detailed findings on the disrupted structural brain connectivity in 16p11.2 deletion syndrome (patients: N = 21, age range: 8-16 years; typically developing (TD) controls: 18, 9-16 years) using structural and diffusion MRI. We performed global short-, middle-, long-range, and interhemispheric connectivity analysis in the whole brain using gyral topology-based cortical parcellation...
April 9, 2018: Brain Imaging and Behavior
https://www.readbyqxmd.com/read/29628467/targeted-therapy-according-to-next-generation-sequencing-based-panel-sequencing
#16
Motonobu Saito, Tomoyuki Momma, Koji Kono
Targeted therapy against actionable gene mutations shows a significantly higher response rate as well as longer survival compared to conventional chemotherapy, and has become a standard therapy for many cancers. Recent progress in next-generation sequencing (NGS) has enabled to identify huge number of genetic aberrations. Based on sequencing results, patients recommend to undergo targeted therapy or immunotherapy. In cases where there are no available approved drugs for the genetic mutations detected in the patients, it is recommended to be facilitate the registration for the clinical trials...
April 7, 2018: Fukushima Journal of Medical Science
https://www.readbyqxmd.com/read/29624756/sex-chromosome-repeats-tip-the-balance-towards-speciation
#17
Michael J O'Neill, Rachel J O'Neill
Because sex chromosomes, by definition, carry genes that determine sex, mutations that alter their structural and functional stability can have immediate consequences for the individual by reducing fertility, but also for a species by altering the sex ratio. Moreover, the sex-specific segregation patterns of heteromorphic sex chromosomes make them havens for selfish genetic elements that not only create sub-optimal sex ratios, but can also foster sexual antagonism. Compensatory mutations to mitigate antagonism or return sex ratios to a Fisherian optimum can create hybrid incompatibility and establish reproductive barriers leading to species divergence...
April 6, 2018: Molecular Ecology
https://www.readbyqxmd.com/read/29622783/genetics-of-male-infertility
#18
REVIEW
Csilla Krausz, Antoni Riera-Escamilla
Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing...
April 5, 2018: Nature Reviews. Urology
https://www.readbyqxmd.com/read/29621297/icopydav-integrated-platform-for-copy-number-variations-detection-annotation-and-visualization
#19
Prashanthi Dharanipragada, Sriharsha Vogeti, Nita Parekh
Discovery of copy number variations (CNVs), a major category of structural variations, have dramatically changed our understanding of differences between individuals and provide an alternate paradigm for the genetic basis of human diseases. CNVs include both copy gain and copy loss events and their detection genome-wide is now possible using high-throughput, low-cost next generation sequencing (NGS) methods. However, accurate detection of CNVs from NGS data is not straightforward due to non-uniform coverage of reads resulting from various systemic biases...
2018: PloS One
https://www.readbyqxmd.com/read/29621252/xome-blender-a-novel-cancer-genome-simulator
#20
Roberto Semeraro, Valerio Orlandini, Alberto Magi
The adoption of next generation sequencing based methods in cancer research allowed for the investigation of the complex genetic structure of tumor samples. In the last few years, considerable importance was given to the research of somatic variants and several computational approaches were developed for this purpose. Despite continuous improvements to these programs, the validation of their results it's a hard challenge due to multiple sources of error. To overcome this drawback different simulation approaches are used to generate synthetic samples but they are often based on the addition of artificial mutations that mimic the complexity of genomic variations...
2018: PloS One
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