Transmission Distortion and Genetic Incompatibilities Between Alleles in A
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Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants. -
A Genome-Wide Association Study of Bisphosphonate-Associated
Calcifed Tissue International (2019) 105:51–67 https://doi.org/10.1007/s00223-019-00546-9 ORIGINAL RESEARCH A Genome‑Wide Association Study of Bisphosphonate‑Associated Atypical Femoral Fracture Mohammad Kharazmi1 · Karl Michaëlsson1 · Jörg Schilcher2 · Niclas Eriksson3,4 · Håkan Melhus3 · Mia Wadelius3 · Pär Hallberg3 Received: 8 January 2019 / Accepted: 8 April 2019 / Published online: 20 April 2019 © The Author(s) 2019 Abstract Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation- wide basis. We compared atypical femoral fracture cases (n = 51) with population-based controls (n = 4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n = 324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide signifcance threshold of p < 5 × 10−8 was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (signifcance threshold of p < 5.7 × 10−6). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. -
Invited Review: Genetic and Genomic Mouse Models for Livestock Research
Archives Animal Breeding – serving the animal science community for 60 years Arch. Anim. Breed., 61, 87–98, 2018 https://doi.org/10.5194/aab-61-87-2018 Open Access © Author(s) 2018. This work is distributed under the Creative Commons Attribution 4.0 License. Archives Animal Breeding Invited review: Genetic and genomic mouse models for livestock research Danny Arends, Deike Hesse, and Gudrun A. Brockmann Albrecht Daniel Thaer-Institut für Agrar- und Gartenbauwissenschaften, Humboldt-Universität zu Berlin, 10115 Berlin, Germany Correspondence: Danny Arends ([email protected]) and Gudrun A. Brockmann ([email protected]) Received: 7 December 2017 – Revised: 3 January 2018 – Accepted: 8 January 2018 – Published: 13 February 2018 Abstract. Knowledge about the function and functioning of single or multiple interacting genes is of the utmost significance for understanding the organism as a whole and for accurate livestock improvement through genomic selection. This includes, but is not limited to, understanding the ontogenetic and environmentally driven regula- tion of gene action contributing to simple and complex traits. Genetically modified mice, in which the functions of single genes are annotated; mice with reduced genetic complexity; and simplified structured populations are tools to gain fundamental knowledge of inheritance patterns and whole system genetics and genomics. In this re- view, we briefly describe existing mouse resources and discuss their value for fundamental and applied research in livestock. 1 Introduction the generation of targeted mutations found their way from model animals to livestock species. Through this progress, During the last 10 years, tools for genome analyses model organisms attain a new position in fundamental sci- have developed tremendously. -
Accuracy of Immunofluorescence in the Diagnosis of Primary Ciliary Dyskinesia
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by UCL Discovery Accuracy of immunofluorescence in the diagnosis of Primary Ciliary Dyskinesia Amelia Shoemark1,2, Emily Frost 1, Mellisa Dixon 1, Sarah Ollosson 1, Kate Kilpin1, Andrew V Rogers 1 , Hannah M Mitchison3, Andrew Bush1,2, Claire Hogg1 1 Department of Paediatrics, Royal Brompton & Harefield NHS Trust, London, UK 2 National Heart and Lung Institute, Imperial College London, UK 3 Genetics and Genomic Medicine Programme, Institute of Child Health, University College London, UK Correspondence to: Amelia Shoemark Primary Ciliary Dyskinesia Service Electron microscopy unit Department of Paediatrics Royal Brompton Hospital London SW3 6NP Statement of contribution: AS, CH and AB designed the study. EF, KK, SO and AS consented patients, conducted light microscopy, collected nasal brushings and prepared slides. EF and AS conducted IF staining and analysis. MD conducted light and electron microscopy. HM provided genotyping. AS and EF analysed the data. AS, CH and AB drafted the manuscript. All authors contributed to manuscript drafts and preparation. AS is custodian of the data and takes responsibility for its accuracy. Sources of support: This project is funded by a NIHR fellowship awarded to AS and mentored by CH, HM and AB. AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London Running head: Immunofluorescence in PCD diagnosis Descriptor number:14.6 Rare paediatric lung disease Word count (excluding abstract and references): 2872 At a Glance Commentary: Scientific Knowledge on the Subject Primary Ciliary Dyskinesia is a genetically heterogeneous chronic condition. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Ciliopathies Gene Panel
Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases. -
NME8 Rs2718058 Polymorphism with Alzheimer's Disease Risk
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 24 Research Paper NME8 rs2718058 polymorphism with Alzheimer’s disease risk: a replication and meta-analysis Shu-Lei Liu1, Xue-Chun Wang2, Meng-Shan Tan1, Hui-Fu Wang1, Wei Zhang1, Zi-Xuan Wang1, Jin-Tai Yu1, Lan Tan1 1Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China 2Department of Radiology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, PR China Correspondence to: Lan Tan, email: [email protected] Jin-Tai Yu, email: [email protected] Keywords: NME8, Alzheimer’s disease, association study, polymorphism, meta-analysis Received: March 01, 2016 Accepted: April 11, 2016 Published: April 28, 2016 ABSTRACT Recently, a large meta-analysis of five genome wide association studies (GWAS) has identified that a novel single nucleotide polymorphism (SNP) rs2718058, adjacent to gene NME8 on chromosome 7p14.1, was associated with late-onset Alzheimer’s disease (LOAD) in Caucasians. However, the effect of rs2718058 on other populations remains unclear. In order to explore the relationship between rs2718058 and LOAD risk in a North Han Chinese population, we recruited 984 LOAD cases and 1354 healthy controls that matched for sex and age in this study. The results showed no significant differences in the genotypic or allelic distributions of rs2718058 polymorphism between LOAD cases and healthy controls, even though after stratification forAPOE ε4 status and statistical adjustment for age, gender and APOE ε4 status (p > 0.05). However, a meta-analysis conducted in a sample of 82513 individuals confirmed a significant association between SNP rs2718058 and LOAD risk (OR = 1.08, 95%CI = 1.05–1.11) in the whole population. -
Genome-Wide Copy Number Variant Analysis For
An et al. BMC Medical Genomics (2016) 9:2 DOI 10.1186/s12920-015-0163-4 RESEARCH ARTICLE Open Access Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population Yu An1,2,4, Wenyuan Duan3, Guoying Huang4, Xiaoli Chen5,LiLi5, Chenxia Nie6, Jia Hou4, Yonghao Gui4, Yiming Wu1, Feng Zhang2, Yiping Shen7, Bailin Wu1,4,7* and Hongyan Wang8* Abstract Background: Ventricular septal defects (VSDs) constitute the most prevalent congenital heart disease (CHD), occurs either in isolation (isolated VSD) or in combination with other cardiac defects (complex VSD). Copy number variation (CNV) has been highlighted as a possible contributing factor to the etiology of many congenital diseases. However, little is known concerning the involvement of CNVs in either isolated or complex VSDs. Methods: We analyzed 154 unrelated Chinese individuals with VSD by chromosomal microarray analysis. The subjects were recruited from four hospitals across China. Each case underwent clinical assessment to define the type of VSD, either isolated or complex VSD. CNVs detected were categorized into syndrom related CNVs, recurrent CNVs and rare CNVs. Genes encompassed by the CNVs were analyzed using enrichment and pathway analysis. Results: Among 154 probands, we identified 29 rare CNVs in 26 VSD patients (16.9 %, 26/154) and 8 syndrome-related CNVs in 8 VSD patients (5.2 %, 8/154). 12 of the detected 29 rare CNVs (41.3 %) were recurrently reported in DECIPHER or ISCA database as associated with either VSD or general heart disease. Fifteen genes (5 %, 15/285) within CNVs were associated with a broad spectrum of complicated CHD. -
Supporting Information
Supporting Information Seo et al. 10.1073/pnas.0910268107 SI Materials and Methods of Iowa Proteomics Facility and analyzed with LTQ XL linear Plasmids and Antibodies. All expression plasmids were constructed ion trap mass spectrometer (Thermo Scientific). with human BBS genes in pCS2 and phCMV2 backbone with fi fi fi indicated tags at the N terminus. Deletion and point mutagenesis Tandem Af nity Puri cation. Constructs for tandem af nity puri- fi was performed using PfuUltra II Fusion HS DNA polymerase cation of BBS5 and BBS7 were generated with N-terminal (Stratagene) and appropriate primers (Integrated DNA Tech- 3xFLAG tag and S tag in CS2 plasmid (FS-BBS5 and FS-BBS7, nology). Primer sequences are available upon request. For RNAi respectively). Stable HEK293T cell lines expressing these genes of BBS6 and BBS12, we generated stable HEK293T cell lines were established and proteins associated with BBS5 and BBS7 fi fi expressing shRNAs against these genes (GIPZ shRNAmir; were tandem af nity puri ed using anti-FLAG and S-protein OpenBiosystems). Expression of BBS10, CCT1, CCT2, and (Novagen) affinity gels. Others are same as above. Protein CCT3 was blocked by transient transfection of siRNAs (ON- identities were determined by Western blotting. TARGETplus SMARTpool; Dharmacon). For RNAi control, we used Nonsilencing GIPZ vector (OpenBiosystems) and ON- Quantitative RT-PCR. Total RNA was extracted from HEK293T TARGETplus Non-Targeting Pool siRNAs (Dharmacon). Anti- cells or mouse testis and eye with TRIzol Reagent (Invitrogen) ’ μ bodies against BBS1, BBS2, BBS4, and BBS7 were described following the manufacturer s instructions. A 1- g quantity of previously (1). -
Genetics of Gene Expression in Primary Immune Cells Identifies Cell
ARTICLES Genetics of gene expression in primary immune cells identifies cell type–specific master regulators and roles of HLA alleles Benjamin P Fairfax1, Seiko Makino1, Jayachandran Radhakrishnan1, Katharine Plant1, Stephen Leslie2, Alexander Dilthey3, Peter Ellis4, Cordelia Langford4, Fredrik O Vannberg1,5 & Julian C Knight1 Trans-acting genetic variants have a substantial, albeit poorly characterized, role in the heritable determination of gene expression. Using paired purified primary monocytes and B cells, we identify new predominantly cell type–specific cis and trans expression quantitative trait loci (eQTLs), including multi-locus trans associations to LYZ and KLF4 in monocytes and B cells, respectively. Additionally, we observe a B cell–specific trans association of rs11171739 at 12q13.2, a known autoimmune disease locus, with IP6K2 (P = 5.8 × 10−15), PRIC285 (P = 3.0 × 10−10) and an upstream region of CDKN1A (P = 2 × 10−52), suggesting roles for cell cycle regulation and peroxisome proliferator-activated receptor γ (PPARγ) signaling in autoimmune pathogenesis. We also find that specific human leukocyte antigen (HLA) alleles form trans associations with the expression of AOAH and ARHGAP24 in monocytes but not in B cells. In summary, we show that mapping gene expression in defined primary cell populations identifies new cell type–specific trans-regulated networks and provides insights into the genetic basis of disease susceptibility. Defining the genetic determinants of gene expression is crucial to especially pertinent in the elucidation of trans-acting eQTLs, where understanding the biological and medical significance of genetic var- context specificity may be of greater relevance12. iation. This is particularly relevant in the drive to identify functional Here we sought to determine cell type–specific eQTLs relevant to variants underlying observed disease associations from genome- immunity and inflammation in paired samples of primary monocytes wide association studies (GWAS)1. -
Knockdown of the BBS10 Gene Product
ndrom Sy es tic & e G n e e n G e f T o Zacchia et al., J Genet Syndr Gene Ther 2014, 5:3 Journal of Genetic Syndromes h l e a r n a DOI: 10.4172/2157-7412.1000222 r p u y o J ISSN: 2157-7412 & Gene Therapy Research Article Open Access Knockdown of the BBS10 Gene Product Affects Apical Targeting of AQP2 in Renal Cells: A Possible Explanation for the Polyuria Associated with Bardet-Biedl Syndrome Miriam Zacchia1, Gabriella Esposito2,3, Monica Carmosino7, Claudia Barbieri7, Enza Zacchia1,5, Alessia Anna Crispo2, Tiziana Fioretti2,3, Francesco Trepiccione1, Valentina Di Iorio6, Francesca Simonelli6, Francesco Salvatore2,4, Giovambattista Capasso1, Maria Svelto7,8 and Giuseppe Procino7,8* 1Chair of Nephrology, Second University of Naples, Italy 2CEINGE-Biotecnologie Avanzate s.c. a r.l., Naples, Italy 3Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Italy 4IRCCS SDN Foundation Naples, Italy 5Institute of Genetics and Biophysics of the National Research Council (CNR), Naples, Italy 6Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences - Second University of Naples, Italy 7Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Italy 8Center of Excellence in Comparative Genomics, Bari, Italy Abstract Objective: Bardet-Biedl syndrome (BBS) is a rare genetic disorder whose clinical features include renal abnormalities, which ranges from renal malformations to renal failure. Polyuria and iso-hyposthenuria are common renal dysfunctions in BBS patients even in the presence of normal GFR. The mechanism underlying this defect is unknown and no genotype-phenotype correlation has yet been reported. -
Coding RNA Genes
Review A guide to naming human non-coding RNA genes Ruth L Seal1,2,* , Ling-Ling Chen3, Sam Griffiths-Jones4, Todd M Lowe5, Michael B Mathews6, Dawn O’Reilly7, Andrew J Pierce8, Peter F Stadler9,10,11,12,13, Igor Ulitsky14 , Sandra L Wolin15 & Elspeth A Bruford1,2 Abstract working on non-coding RNA (ncRNA) nomenclature in the mid- 1980s with the approval of initial gene symbols for mitochondrial Research on non-coding RNA (ncRNA) is a rapidly expanding field. transfer RNA (tRNA) genes. Since then, we have worked closely Providing an official gene symbol and name to ncRNA genes brings with experts in the ncRNA field to develop symbols for many dif- order to otherwise potential chaos as it allows unambiguous ferent kinds of ncRNA genes. communication about each gene. The HUGO Gene Nomenclature The number of genes that the HGNC has named per ncRNA class Committee (HGNC, www.genenames.org) is the only group with is shown in Fig 1, and ranges in number from over 4,500 long the authority to approve symbols for human genes. The HGNC ncRNA (lncRNA) genes and over 1,900 microRNA genes, to just four works with specialist advisors for different classes of ncRNA to genes in the vault and Y RNA classes. Every gene symbol has a ensure that ncRNA nomenclature is accurate and informative, Symbol Report on our website, www.genenames.org, which where possible. Here, we review each major class of ncRNA that is displays the gene symbol, gene name, chromosomal location and currently annotated in the human genome and describe how each also includes links to key resources such as Ensembl (Zerbino et al, class is assigned a standardised nomenclature.