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Haddadi G, Lam B, Akhtar S, Yavelberg L, Jamnik V, Roudier E. The MDM2 SNP309 differentially impacts cardiorespiratory fitness in young healthy women and men. Eur J Appl Physiol 2025; 125:1371-1383. [PMID: 39681743 DOI: 10.1007/s00421-024-05682-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 11/25/2024] [Indexed: 12/18/2024]
Abstract
PURPOSE Maximal oxygen consumption (VO2max), the predominant index of cardiorespiratory fitness (CRF), is a predictor of whole-body function and longevity in humans. The central cardiac function and the skeletal muscle's capacity to use oxygen are key determinants of VO2max. Murine Double Minute 2 (MDM2), mainly known as an oncogene, could regulate myocardial hypertrophy, skeletal muscle angiogenesis, and oxidative phosphorylation. A prevalent single nucleotide polymorphism in the MDM2 promoter (SNP309) substitutes a T for a G, supporting a greater transcriptional activity. We aim to assess whether SNP309 impacts intrinsic CRF. METHODS 82 young healthy nonathletic male and female adults aged 23 ± 2 years performed cardiorespiratory exercise testing to determine their VO2max (mL kg-1 min-1). The genomic DNAs isolated from saliva were genotyped using Taqman-based qPCR. RESULTS A one-way ANOVA showed that SNP309 influenced relative VO2max in the whole cohort (p = 0.044) and in men (p = 0.009), remaining non-significant in women (p = 0.133). VO2max was higher in TT homozygotes than in GT heterozygotes (whole cohort, 47 ± 12 vs. 42 ± 6 mL kg-1 min-1, p = 0.030; men, 53 ± 8 vs. 45 ± 6 mL kg-1 min-1, p = 0.011). A contingency analysis revealed a positive association between SNP309 in men in which the TT genotype was more frequent in the high VO2max group (p = 0.006). When considering G as the dominant allele, men bearing a G allele had lower relative VO2max than TT homozygotes (47 ± 7 vs. 53 ± 8, GG/GT vs. TT, p = 0.010). Conversely, women bearing a G allele had a higher relative VO2max than TT homozygotes (39 ± 5 vs. 34 ± 7, GG/GT vs. TT, p = 0.047). CONCLUSION SNP309 impacts VO2max in a sex-dependent manner in our cohort.
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Affiliation(s)
- Ghazal Haddadi
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Brian Lam
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Sokaina Akhtar
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Loren Yavelberg
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Veronica Jamnik
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada
| | - Emilie Roudier
- School of Kinesiology and Health Science, Faculty of Health, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada.
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Pei Y, Tanguy M, Giess A, Dixit A, Wilson LC, Gibbons RJ, Twigg SRF, Elgar G, Wilkie AOM. A Comparison of Structural Variant Calling from Short-Read and Nanopore-Based Whole-Genome Sequencing Using Optical Genome Mapping as a Benchmark. Genes (Basel) 2024; 15:925. [PMID: 39062704 PMCID: PMC11276380 DOI: 10.3390/genes15070925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 07/03/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
The identification of structural variants (SVs) in genomic data represents an ongoing challenge because of difficulties in reliable SV calling leading to reduced sensitivity and specificity. We prepared high-quality DNA from 9 parent-child trios, who had previously undergone short-read whole-genome sequencing (Illumina platform) as part of the Genomics England 100,000 Genomes Project. We reanalysed the genomes using both Bionano optical genome mapping (OGM; 8 probands and one trio) and Nanopore long-read sequencing (Oxford Nanopore Technologies [ONT] platform; all samples). To establish a "truth" dataset, we asked whether rare proband SV calls (n = 234) made by the Bionano Access (version 1.6.1)/Solve software (version 3.6.1_11162020) could be verified by individual visualisation using the Integrative Genomics Viewer with either or both of the Illumina and ONT raw sequence. Of these, 222 calls were verified, indicating that Bionano OGM calls have high precision (positive predictive value 95%). We then asked what proportion of the 222 true Bionano SVs had been identified by SV callers in the other two datasets. In the Illumina dataset, sensitivity varied according to variant type, being high for deletions (115/134; 86%) but poor for insertions (13/58; 22%). In the ONT dataset, sensitivity was generally poor using the original Sniffles variant caller (48% overall) but improved substantially with use of Sniffles2 (36/40; 90% and 17/23; 74% for deletions and insertions, respectively). In summary, we show that the precision of OGM is very high. In addition, when applying the Sniffles2 caller, the sensitivity of SV calling using ONT long-read sequence data outperforms Illumina sequencing for most SV types.
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Affiliation(s)
- Yang Pei
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; (Y.P.); (S.R.F.T.)
| | - Melanie Tanguy
- Genomics England Limited, One Canada Square, London E14 5AB, UK
| | - Adam Giess
- Genomics England Limited, One Canada Square, London E14 5AB, UK
| | - Abhijit Dixit
- Clinical Genetics Service, Nottingham University Hospitals NHS Foundation Trust, City Hospital, Nottingham NG5 1PB, UK
| | - Louise C. Wilson
- North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London WC1N 3JH, UK
| | - Richard J. Gibbons
- MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Stephen R. F. Twigg
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; (Y.P.); (S.R.F.T.)
| | - Greg Elgar
- Genomics England Limited, One Canada Square, London E14 5AB, UK
| | - Andrew O. M. Wilkie
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; (Y.P.); (S.R.F.T.)
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Ameli A, Peña-Castillo L, Usefi H. Assessing the reproducibility of machine-learning-based biomarker discovery in Parkinson's disease. Comput Biol Med 2024; 174:108407. [PMID: 38603902 DOI: 10.1016/j.compbiomed.2024.108407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/21/2024] [Accepted: 04/01/2024] [Indexed: 04/13/2024]
Abstract
Feature selection and machine learning algorithms can be used to analyze Single Nucleotide Polymorphisms (SNPs) data and identify potential disease biomarkers. Reproducibility of identified biomarkers is critical for them to be useful for clinical research; however, genotyping platforms and selection criteria for individuals to be genotyped affect the reproducibility of identified biomarkers. To assess biomarkers reproducibility, we collected five SNPs datasets from the database of Genotypes and Phenotypes (dbGaP) and explored several data integration strategies. While combining datasets can lead to a reduction in classification accuracy, it has the potential to improve the reproducibility of potential biomarkers. We evaluated the agreement among different strategies in terms of the SNPs that were identified as potential Parkinson's disease (PD) biomarkers. Our findings indicate that, on average, 93% of the SNPs identified in a single dataset fail to be identified in other datasets. However, through dataset integration, this lack of replication is reduced to 62%. We discovered fifty SNPs that were identified at least twice, which could potentially serve as novel PD biomarkers. These SNPs are indirectly linked to PD in the literature but have not been directly associated with PD before. These findings open up new potential avenues of investigation.
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Affiliation(s)
- Ali Ameli
- Department of Computer Science, Memorial University of Newfoundland, 230 Elizabeth Ave, St. John's, A1C5S7, NL, Canada
| | - Lourdes Peña-Castillo
- Department of Computer Science, Memorial University of Newfoundland, 230 Elizabeth Ave, St. John's, A1C5S7, NL, Canada; Department of Biology, Memorial University of Newfoundland, 230 Elizabeth Ave, St. John's, A1C5S7, NL, Canada.
| | - Hamid Usefi
- Department of Computer Science, Memorial University of Newfoundland, 230 Elizabeth Ave, St. John's, A1C5S7, NL, Canada; Department of Mathematics and Statistics, Memorial University of Newfoundland, 230 Elizabeth Ave, St. John's, A1C5S7, NL, Canada.
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Al-Mousa H, Barbouche MR. Genetics of Inborn Errors of Immunity in highly consanguineous Middle Eastern and North African populations. Semin Immunol 2023; 67:101763. [PMID: 37075586 DOI: 10.1016/j.smim.2023.101763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics.
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Affiliation(s)
- Hamoud Al-Mousa
- Section of Allergy and Immunology, Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
| | - Mohamed-Ridha Barbouche
- Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
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Hallacli E, Kayatekin C, Nazeen S, Wang XH, Sheinkopf Z, Sathyakumar S, Sarkar S, Jiang X, Dong X, Di Maio R, Wang W, Keeney MT, Felsky D, Sandoe J, Vahdatshoar A, Udeshi ND, Mani DR, Carr SA, Lindquist S, De Jager PL, Bartel DP, Myers CL, Greenamyre JT, Feany MB, Sunyaev SR, Chung CY, Khurana V. The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability. Cell 2022; 185:2035-2056.e33. [PMID: 35688132 DOI: 10.1016/j.cell.2022.05.008] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 04/05/2022] [Accepted: 05/06/2022] [Indexed: 12/13/2022]
Abstract
Alpha-synuclein (αS) is a conformationally plastic protein that reversibly binds to cellular membranes. It aggregates and is genetically linked to Parkinson's disease (PD). Here, we show that αS directly modulates processing bodies (P-bodies), membraneless organelles that function in mRNA turnover and storage. The N terminus of αS, but not other synucleins, dictates mutually exclusive binding either to cellular membranes or to P-bodies in the cytosol. αS associates with multiple decapping proteins in close proximity on the Edc4 scaffold. As αS pathologically accumulates, aberrant interaction with Edc4 occurs at the expense of physiologic decapping-module interactions. mRNA decay kinetics within PD-relevant pathways are correspondingly disrupted in PD patient neurons and brain. Genetic modulation of P-body components alters αS toxicity, and human genetic analysis lends support to the disease-relevance of these interactions. Beyond revealing an unexpected aspect of αS function and pathology, our data highlight the versatility of conformationally plastic proteins with high intrinsic disorder.
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Affiliation(s)
- Erinc Hallacli
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Can Kayatekin
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Sumaiya Nazeen
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
| | - Xiou H Wang
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Zoe Sheinkopf
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Shubhangi Sathyakumar
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Souvarish Sarkar
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Xin Jiang
- Yumanity Therapeutics, Boston, MA 02135, USA
| | - Xianjun Dong
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Genomics and Bioinformatics Hub, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
| | - Roberto Di Maio
- Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, Pittsburgh, PA 15213, USA
| | - Wen Wang
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - Matthew T Keeney
- Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, Pittsburgh, PA 15213, USA
| | - Daniel Felsky
- Krembil Centre for Neuroinformatics and Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, 155 College Street, Toronto, ON M5T 3M7, Canada
| | - Jackson Sandoe
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
| | - Aazam Vahdatshoar
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | | | - D R Mani
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Steven A Carr
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Susan Lindquist
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA
| | - Philip L De Jager
- Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - David P Bartel
- Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA
| | - Chad L Myers
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA
| | - J Timothy Greenamyre
- Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, Pittsburgh, PA 15213, USA
| | - Mel B Feany
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Shamil R Sunyaev
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115
| | | | - Vikram Khurana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Division of Movement Disorders, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
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Datta S, Patel M, Kashyap S, Patel D, Singh U. Chimeric chromosome landscapes of human somatic cell cultures show dependence on stress and regulation of genomic repeats by CGGBP1. Oncotarget 2022; 13:136-155. [PMID: 35070079 PMCID: PMC8765472 DOI: 10.18632/oncotarget.28174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 12/20/2021] [Indexed: 11/25/2022] Open
Abstract
Genomes of somatic cells in culture are prone to spontaneous mutations due to errors in replication and DNA repair. Some of these errors, such as chromosomal fusions, are not rectifiable and subject to selection or elimination in growing cultures. Somatic cell cultures are thus expected to generate background levels of potentially stable chromosomal chimeras. A description of the landscape of such spontaneously generated chromosomal chimeras in cultured cells will help understand the factors affecting somatic mosaicism. Here we show that short homology-associated non-homologous chromosomal chimeras occur in normal human fibroblasts and HEK293T cells at genomic repeats. The occurrence of chromosomal chimeras is enhanced by heat stress and depletion of a repeat regulatory protein CGGBP1. We also present evidence of homologous chromosomal chimeras between allelic copies in repeat-rich DNA obtained by methylcytosine immunoprecipitation. The formation of homologous chromosomal chimeras at Alu and L1 repeats increases upon depletion of CGGBP1. Our data are derived from de novo sequencing from three different cell lines under different experimental conditions and our chromosomal chimera detection pipeline is applicable to long as well as short read sequencing platforms. These findings present significant information about the generation, sensitivity and regulation of somatic mosaicism in human cell cultures.
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Affiliation(s)
- Subhamoy Datta
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
| | - Manthan Patel
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, UK
| | - Sukesh Kashyap
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
| | - Divyesh Patel
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
- Current address: Research Programs Unit, Applied Tumor Genomics Program, Faculty of Medicine, University of Helsinki, Biomedicum, Helsinki 00290, Finland
| | - Umashankar Singh
- HoMeCell Lab, Discipline of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, Gujarat 382355, India
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El Bitar F, Al Sudairy N, Qadi N, Al Rajeh S, Alghamdi F, Al Amari H, Al Dawsari G, Alsubaie S, Al Sudairi M, Abdulaziz S, Al Tassan N. A Comprehensive Analysis of Unique and Recurrent Copy Number Variations in Alzheimer's Disease and its Related Disorders. Curr Alzheimer Res 2020; 17:926-938. [PMID: 33256577 DOI: 10.2174/1567205017666201130111424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 08/20/2020] [Accepted: 10/29/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Copy number variations (CNVs) play an important role in the genetic etiology of various neurological disorders, including Alzheimer's disease (AD). Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) were shown to have share mechanisms and signaling pathways with AD. OBJECTIVE We aimed to assess CNVs regions that may harbor genes contributing to AD, T2DM, and MDD in 67 Saudi familial and sporadic AD patients, with no alterations in the known genes of AD and genotyped previously for APOE. METHODS DNA was analyzed using the CytoScan-HD array. Two layers of filtering criteria were applied. All the identified CNVs were checked in the Database of Genomic Variants (DGV). RESULTS A total of 1086 CNVs (565 gains and 521 losses) were identified in our study. We found 73 CNVs harboring genes that may be associated with AD, T2DM or MDD. Nineteen CNVs were novel. Most importantly, 42 CNVs were unique in our studied cohort existing only in one patient. Two large gains on chromosomes 1 and 13 harbored genes implicated in the studied disorders. We identified CNVs in genes that encode proteins involved in the metabolism of amyloid-β peptide (AGRN, APBA2, CR1, CR2, IGF2R, KIAA0125, MBP, RER1, RTN4R, VDR and WISPI) or Tau proteins (CACNAIC, CELF2, DUSP22, HTRA1 and SLC2A14). CONCLUSION The present work provided information on the presence of CNVs related to AD, T2DM, and MDD in Saudi Alzheimer's patients.
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Affiliation(s)
- Fadia El Bitar
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nourah Al Sudairy
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Najeeb Qadi
- Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Fatimah Alghamdi
- Institute of Biology and Environmental Research, National Center for Biotechnology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Hala Al Amari
- Institute of Biology and Environmental Research, National Center for Biotechnology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Ghadeer Al Dawsari
- Institute of Biology and Environmental Research, National Center for Genomics Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Sahar Alsubaie
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mishael Al Sudairi
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sara Abdulaziz
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nada Al Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Toral-Lopez J, Huerta LMG, Messina-Baas O, Cuevas-Covarrubias SA. Submicroscopic 11p13 deletion including the elongator acetyltransferase complex subunit 4 gene in a girl with language failure, intellectual disability and congenital malformations: A case report. World J Clin Cases 2020; 8:5296-5303. [PMID: 33269262 PMCID: PMC7674752 DOI: 10.12998/wjcc.v8.i21.5296] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/08/2020] [Accepted: 09/18/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND We described the main features of an infant diagnosed with facial dysmorphic, language failure, intellectual disability and congenital malformations to strengthen our understanding of the disease. Currently, treatment is only rehabilitation and surgery for cleft lip and palate. CASE SUMMARY The proband was a 2-years-8-months-old girl. Familial history was negative for congenital malformations or intellectual disability. The patient had microcephaly, upward-slanting palpebral fissures, depressed nasal bridge, bulbous nose and bilateral cleft lip and palate. Brain magnetic resonance imaging showed cortical atrophy and band heterotopia. Her motor and intellectual development is delayed. A submicroscopic deletion in 11p13 involving the elongator acetyltransferase complex subunit 4 gene (ELP4) and a loss of heterozygosity in Xq25-q26.3 were detected. CONCLUSION There is no treatment for the ELP4 deletion caused by a submicroscopic 11p3 deletion. We describe a second case of deletion of the ELP4 gene without aniridia, which confirms the association between ELP4 gene with several defects and absence of this ocular defect. Additional clinical data in the deletion of the ELP4 gene as cleft palate, facial dysmorphism, and changes at level brain could be associated to this gene or be part of the effect of the recessives genes involved in the loss of heterozygosity region of Xq25-26.3.
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Affiliation(s)
- Jaime Toral-Lopez
- Departamento de Genética Medica, Centro Medico Ecatepec, ISSEMYM, Ecatepec 55000, México
- Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud/Hospital Infantil de México, Universidad Nacional Autónoma de México, México 06720, México
| | | | - Olga Messina-Baas
- Departamento de Oftalmología, Hospital General de México, Cuauhtémoc 06720, México
| | - Sergio A Cuevas-Covarrubias
- Genetica, Hospital General de México, Cuauhtémoc 06726, Mexico
- Programa de Maestría y Doctorado en Ciencias Médicas, Odontológicas y de la Salud, Universidad Nacional Autónoma de México, México 06720, Mexico
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9
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Zheng T, Zhu X, Zhang X, Zhao Z, Yi X, Wang J, Li H. A machine learning framework for genotyping the structural variations with copy number variant. BMC Med Genomics 2020; 13:79. [PMID: 32854699 PMCID: PMC7450592 DOI: 10.1186/s12920-020-00733-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 05/25/2020] [Indexed: 12/02/2022] Open
Abstract
Background Genotyping of structural variation is an important computational problem in next generation sequence data analysis. However, in cancer genomes, the copy number variant(CNV) often coexists with other types of structural variations which significantly reduces the accuracy of the existing genotype methods. The bias on sequencing coverage and variant allelic frequency can be observed on a CNV region, which leads to the genotyping approaches that misinterpret the heterozygote as a homozygote. Furthermore, other data signals such as split mapped read, abnormal read will also be misjudged because of the CNV. Therefore, genotyping the structural variations with CNV is a complicated computational problem which should consider multiple features and their interactions. Methods Here we proposed a computational method for genotyping indels in the CNV region, which introduced a machine learning framework to comprehensively incorporate a set of data features and their interactions. We extracted fifteen kinds of classification features as input and different from the traditional genotyping problem, here the structure of variant may fall into types of normal homozygote, homozygous variant, heterozygous variant without CNV, heterozygous variant with a CNV on the mutated haplotype, and heterozygous variant with a CNV on the wild haplotype. The Multiclass Relevance Vector Machine (M-RVM) was used as a machine learning framework combined with the distribution characteristics of the features. Results We applied the proposed method to both simulated and real data, and compared it with the existing popular softwares include Gindel, Facets, GATK, and also compared with other machine learning cores: Support Vector Machine, Lanrange-SVM with OVO multiple classification, Naïve Bayes and BP Neural Network. The results demonstrated that the proposed method outperforms others on accuracy, stability and efficiency. Conclusion This work shows that the genotyping of structural variations on the CNV region cannot be solved as a traditional genotyping problem. More features should be used to efficiently complete the five-category task. According to the result, the proposed method can be a practical algorithm to correct genotype structural variations with CNV on the next generation sequence data. The source codes have been uploaded at https://github.com/TrinaZ/Mixgenotypefor academic usage only.
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Affiliation(s)
- Tian Zheng
- School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Xiaoyan Zhu
- School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
| | - Xuanping Zhang
- School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Zhongmeng Zhao
- School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Xin Yi
- Geneplus-Beijing, Beijing, 102206, China
| | - Jiayin Wang
- School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Hongle Li
- Department of Molecular Pathology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450003, China.
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10
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Autism spectrum disorder in a patient with a genomic rearrangement that only involves the EPHA5 gene. Psychiatr Genet 2019; 29:86-90. [DOI: 10.1097/ypg.0000000000000217] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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11
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Matejka K, Stückler F, Salomon M, Ensenauer R, Reischl E, Hoerburger L, Grallert H, Kastenmüller G, Peters A, Daniel H, Krumsiek J, Theis FJ, Hauner H, Laumen H. Dynamic modelling of an ACADS genotype in fatty acid oxidation - Application of cellular models for the analysis of common genetic variants. PLoS One 2019; 14:e0216110. [PMID: 31120904 PMCID: PMC6532850 DOI: 10.1371/journal.pone.0216110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 04/15/2019] [Indexed: 11/19/2022] Open
Abstract
Background Genome-wide association studies of common diseases or metabolite quantitative traits often identify common variants of small effect size, which may contribute to phenotypes by modulation of gene expression. Thus, there is growing demand for cellular models enabling to assess the impact of gene regulatory variants with moderate effects on gene expression. Mitochondrial fatty acid oxidation is an important energy metabolism pathway. Common noncoding acyl-CoA dehydrogenase short chain (ACADS) gene variants are associated with plasma C4-acylcarnitine levels and allele-specific modulation of ACADS expression may contribute to the observed phenotype. Methods and findings We assessed ACADS expression and intracellular acylcarnitine levels in human lymphoblastoid cell lines (LCL) genotyped for a common ACADS variant associated with plasma C4-acylcarnitine and found a significant genotype-dependent decrease of ACADS mRNA and protein. Next, we modelled gradual decrease of ACADS expression using a tetracycline-regulated shRNA-knockdown of ACADS in Huh7 hepatocytes, a cell line with high fatty acid oxidation-(FAO)-capacity. Assessing acylcarnitine flux in both models, we found increased C4-acylcarnitine levels with decreased ACADS expression levels. Moreover, assessing time-dependent changes of acylcarnitine levels in shRNA-hepatocytes with altered ACADS expression levels revealed an unexpected effect on long- and medium-chain fatty acid intermediates. Conclusions Both, genotyped LCL and regulated shRNA-knockdown are valuable tools to model moderate, gradual gene-regulatory effects of common variants on cellular phenotypes. Decreasing ACADS expression levels modulate short and surprisingly also long/medium chain acylcarnitines, and may contribute to increased plasma acylcarnitine levels.
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Affiliation(s)
- Kerstin Matejka
- Chair of Nutritional Medicine, Else Kröner-Fresenius-Center for Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- ZIEL-Research Center for Nutrition and Food Sciences, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Technische Universität München, Freising-Weihenstephan, Germany
| | - Ferdinand Stückler
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | | | - Regina Ensenauer
- Research Center, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-Universität München, München, Germany
- Experimental Pediatrics and Metabolism, Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Institute of Child Nutrition, Max Rubner-Institut, Karlsruhe, Germany
| | - Eva Reischl
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Lena Hoerburger
- Paediatric Nutritional Medicine, Else Kröner-Fresenius-Centre for Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
| | - Harald Grallert
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Technische Universität München, Freising-Weihenstephan, Germany
- Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Gabi Kastenmüller
- Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Annette Peters
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Epidemiology, Helmholtz Zentrum München, Neuherberg, Germany
- German Research Center for Cardiovascular Disease (DZHK-Munich partner site), Neuherberg, Germany
| | - Hannelore Daniel
- ZIEL-Research Center for Nutrition and Food Sciences, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- Chair of Physiology of Human Nutrition, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
| | - Jan Krumsiek
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States of America
| | - Fabian J. Theis
- Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany
- Department of Mathematical Science, Technische Universität München, Garching, Germany
- * E-mail: (FJT); (HL)
| | - Hans Hauner
- Chair of Nutritional Medicine, Else Kröner-Fresenius-Center for Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- ZIEL-Research Center for Nutrition and Food Sciences, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Technische Universität München, Freising-Weihenstephan, Germany
- Else Kröner-Fresenius-Center for Nutritional Medicine, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Helmut Laumen
- Chair of Nutritional Medicine, Else Kröner-Fresenius-Center for Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- ZIEL-Research Center for Nutrition and Food Sciences, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Neuherberg, Germany
- Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Technische Universität München, Freising-Weihenstephan, Germany
- Paediatric Nutritional Medicine, Else Kröner-Fresenius-Centre for Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany
- Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
- Research Unit Protein Science, Helmholtz Zentrum München, Neuherberg, Germany
- * E-mail: (FJT); (HL)
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12
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Remacha L, Pirman D, Mahoney CE, Coloma J, Calsina B, Currás-Freixes M, Letón R, Torres-Pérez R, Richter S, Pita G, Herráez B, Cianchetta G, Honrado E, Maestre L, Urioste M, Aller J, García-Uriarte Ó, Gálvez MÁ, Luque RM, Lahera M, Moreno-Rengel C, Eisenhofer G, Montero-Conde C, Rodríguez-Antona C, Llorca Ó, Smolen GA, Robledo M, Cascón A. Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas. Am J Hum Genet 2019; 104:651-664. [PMID: 30929736 PMCID: PMC6451733 DOI: 10.1016/j.ajhg.2019.02.017] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 02/14/2019] [Indexed: 12/21/2022] Open
Abstract
Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13C5-glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals (∼7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.
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Affiliation(s)
- Laura Remacha
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - David Pirman
- Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA
| | | | - Javier Coloma
- Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Bruna Calsina
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Maria Currás-Freixes
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Rocío Letón
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Rafael Torres-Pérez
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Susan Richter
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Freistaat Sachsen 01069, Germany
| | - Guillermo Pita
- Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Belén Herráez
- Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | | | - Emiliano Honrado
- Anatomical Pathology Service, Hospital of León, León, Castilla y León 24071, Spain
| | - Lorena Maestre
- Monoclonal Antibodies Unit, Biotechnology Programme, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Miguel Urioste
- Familial Cancer Clinical Unit, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Javier Aller
- Department of Endocrinology, University Hospital Puerta de Hierro, Majadahonda, Madrid 28222, Spain
| | - Óscar García-Uriarte
- Nephrology Department, University Hospital of Araba, Vitoria, País Vasco 01009, Spain
| | - María Ángeles Gálvez
- Service of Endocrinology and Nutrition, University Hospital Reina Sofía, Córdoba, Andalucía 14004, Spain; Maimónides Institute of Biomedical Research of Cordoba, Córdoba, Andalucía 14004, Spain
| | - Raúl M Luque
- Hormones and Cancer Group, Maimónides Institute of Biomedical Research of Córdoba, Córdoba, Andalucía 14004, Spain
| | - Marcos Lahera
- Endocrinology and Nutrition Department, La Princesa University Hospital, Madrid, Madrid 28006, Spain
| | - Cristina Moreno-Rengel
- Department of Endocrinology and Nutrition, University Hospital of Basurto, Bilbao 48013, Spain
| | - Graeme Eisenhofer
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Freistaat Sachsen 01069, Germany
| | - Cristina Montero-Conde
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | - Cristina Rodríguez-Antona
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid 28029, Spain
| | - Óscar Llorca
- Structural Biology Programme, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain
| | | | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid 28029, Spain
| | - Alberto Cascón
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre, Madrid, Madrid 28029, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Madrid 28029, Spain.
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13
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Kun-Rodrigues C, Orme T, Carmona S, Hernandez DG, Ross OA, Eicher JD, Shepherd C, Parkkinen L, Darwent L, Heckman MG, Scholz SW, Troncoso JC, Pletnikova O, Dawson T, Rosenthal L, Ansorge O, Clarimon J, Lleo A, Morenas-Rodriguez E, Clark L, Honig LS, Marder K, Lemstra A, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Serrano GE, Beach TG, Lesage S, Galasko D, Masliah E, Santana I, Pastor P, Diez-Fairen M, Aguilar M, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Pickering-Brown S, Mann D, Halliday GM, Hardy J, Trojanowski JQ, Dickson DW, Singleton A, Stone DJ, Guerreiro R, Bras J. A comprehensive screening of copy number variability in dementia with Lewy bodies. Neurobiol Aging 2019; 75:223.e1-223.e10. [PMID: 30448004 PMCID: PMC6541211 DOI: 10.1016/j.neurobiolaging.2018.10.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 10/15/2018] [Accepted: 10/15/2018] [Indexed: 12/12/2022]
Abstract
The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
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Affiliation(s)
- Celia Kun-Rodrigues
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
| | - Tatiana Orme
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
| | - Susana Carmona
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK
| | - Dena G Hernandez
- Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA; German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany
| | - Owen A Ross
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | - John D Eicher
- Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, USA
| | - Claire Shepherd
- Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Laura Parkkinen
- Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK
| | - Lee Darwent
- UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
| | - Michael G Heckman
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA
| | - Sonja W Scholz
- Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Juan C Troncoso
- Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Olga Pletnikova
- Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ted Dawson
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Liana Rosenthal
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Olaf Ansorge
- Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, UK
| | - Jordi Clarimon
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Alberto Lleo
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Estrella Morenas-Rodriguez
- Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
| | - Lorraine Clark
- Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Lawrence S Honig
- Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Karen Marder
- Taub Institute for Alzheimer Disease and the Aging Brain and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Afina Lemstra
- Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
| | - Ekaterina Rogaeva
- Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, Canada
| | - Peter St George-Hyslop
- Tanz Centre for Research in Neurodegenerative Diseases and Department of Medicine, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
| | - Elisabet Londos
- Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Lund, Sweden
| | - Henrik Zetterberg
- UK Dementia Research Institute at UCL, London UK, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden
| | - Imelda Barber
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
| | - Anne Braae
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
| | - Kristelle Brown
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
| | - Kevin Morgan
- Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK
| | - Claire Troakes
- Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - Safa Al-Sarraj
- Department of Basic and Clinical Neuroscience and Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - Tammaryn Lashley
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Janice Holton
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Yaroslau Compta
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK and Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain
| | - Vivianna Van Deerlin
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | | | | | - Suzanne Lesage
- Inserm U1127, CNRS UMR7225, Sorbonne Universites, Institut du Cerveau et de la Moelle epiniere, Paris, France
| | - Douglas Galasko
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, La Jolla, CA, USA
| | - Eliezer Masliah
- Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Department of Pathology, University of California, San Diego, La Jolla, CA, USA
| | - Isabel Santana
- Neurology Service, University of Coimbra Hospital, Coimbra, Portugal
| | - Pau Pastor
- Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, and Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
| | - Monica Diez-Fairen
- Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, and Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
| | - Miquel Aguilar
- Memory Unit, Department of Neurology, University Hospital Mutua de Terrassa, University of Barcelona, and Fundacio de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
| | - Pentti J Tienari
- Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland
| | - Liisa Myllykangas
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Minna Oinas
- Department of Neuropathology and Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Tamas Revesz
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Andrew Lees
- Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Brad F Boeve
- Neurology Department, Mayo Clinic, Rochester, MN, USA
| | | | - Tanis J Ferman
- Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, USA
| | - Valentina Escott-Price
- MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | | | - Nigel J Cairns
- Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
| | - John C Morris
- Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, USA
| | - Stuart Pickering-Brown
- Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
| | - David Mann
- Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK
| | - Glenda M Halliday
- Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia; Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia
| | - John Hardy
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
| | - John Q Trojanowski
- Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | | | - Andrew Singleton
- Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, USA
| | - David J Stone
- Genetics and Pharmacogenomics, Merck and Co, West Point, PA, USA
| | - Rita Guerreiro
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal
| | - Jose Bras
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute (UK DRI) at UCL, London, UK; Department of Medical Sciences and Institute of Biomedicine, iBiMED, University of Aveiro, Aveiro, Portugal.
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Gennarino VA, Palmer EE, McDonell LM, Wang L, Adamski CJ, Koire A, See L, Chen CA, Schaaf CP, Rosenfeld JA, Panzer JA, Moog U, Hao S, Bye A, Kirk EP, Stankiewicz P, Breman AM, McBride A, Kandula T, Dubbs HA, Macintosh R, Cardamone M, Zhu Y, Ying K, Dias KR, Cho MT, Henderson LB, Baskin B, Morris P, Tao J, Cowley MJ, Dinger ME, Roscioli T, Caluseriu O, Suchowersky O, Sachdev RK, Lichtarge O, Tang J, Boycott KM, Holder JL, Zoghbi HY. A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures. Cell 2019; 172:924-936.e11. [PMID: 29474920 DOI: 10.1016/j.cell.2018.02.006] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 08/23/2017] [Accepted: 02/01/2018] [Indexed: 02/06/2023]
Abstract
Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.
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Affiliation(s)
- Vincenzo A Gennarino
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
| | - Elizabeth E Palmer
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics of Learning Disability Service, Waratah, NSW 2298, Australia
| | - Laura M McDonell
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
| | - Li Wang
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Carolyn J Adamski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
| | - Amanda Koire
- Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lauren See
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Chun-An Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Christian P Schaaf
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jessica A Panzer
- Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ute Moog
- Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 440, 69120 Heidelberg, Germany
| | - Shuang Hao
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ann Bye
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia
| | - Edwin P Kirk
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia
| | - Pawel Stankiewicz
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA
| | - Amy M Breman
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA
| | - Arran McBride
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
| | - Tejaswi Kandula
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia
| | - Holly A Dubbs
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | | | - Michael Cardamone
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia
| | - Ying Zhu
- Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia
| | - Kevin Ying
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Kerith-Rae Dias
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Megan T Cho
- GeneDx, 207 Perry Pkwy Gaithersburg, MD 20877, USA
| | | | | | - Paula Morris
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia
| | - Jiang Tao
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
| | - Mark J Cowley
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
| | - Marcel E Dinger
- Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia
| | - Tony Roscioli
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; Genetics Laboratory, NSW Health Pathology East Randwick, Sydney, NSW, Australia; Neuroscience Research Australia and Prince of Wales Clinical School, University of New South Wales, Randwick, NSW 2031, Australia
| | - Oana Caluseriu
- Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada
| | - Oksana Suchowersky
- Department of Medical Genetics, University of Alberta, AB T6G 2H7, Canada; Departments of Medicine (Neurology) and Pediatrics, University of Alberta, AB, Canada
| | - Rani K Sachdev
- Sydney Children's Hospital, Randwick, NSW 2031, Australia; School of Women's and Children's Health, UNSW Medicine, The University of New South Wales, NSW 2031, Australia
| | - Olivier Lichtarge
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jianrong Tang
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kym M Boycott
- Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada
| | - J Lloyd Holder
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Huda Y Zoghbi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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15
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Scheinfeldt LB, Hodges K, Pevsner J, Berlin D, Turan N, Gerry NP. Genetic and genomic stability across lymphoblastoid cell line expansions. BMC Res Notes 2018; 11:558. [PMID: 30075799 PMCID: PMC6076395 DOI: 10.1186/s13104-018-3664-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 07/30/2018] [Indexed: 11/21/2022] Open
Abstract
Objective Lymphoblastoid cell lines are widely used in genetic and genomic studies. Previous work has characterized variant stability in transformed culture and across culture passages. Our objective was to extend this work to evaluate single nucleotide polymorphism and structural variation across cell line expansions, which are commonly used in biorepository distribution. Our study used DNA and cell lines sampled from six research participants. We assayed genome-wide genetic variants and inferred structural variants for DNA extracted from blood, from transformed cell cultures, and from three generations of expansions. Results Single nucleotide variation was stable between DNA and expanded cell lines (ranging from 99.90 to 99.98% concordance). Structural variation was less consistent across expansions (median 33% concordance) with a noticeable decrease in later expansions. In summary, we demonstrate consistency between SNPs assayed from whole blood DNA and LCL DNA; however, more caution should be taken in using LCL DNA to study structural variation. Electronic supplementary material The online version of this article (10.1186/s13104-018-3664-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Laura B Scheinfeldt
- Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ, 08003, USA.
| | - Kelly Hodges
- Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ, 08003, USA
| | - Jonathan Pevsner
- Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD, 21205, USA
| | - Dorit Berlin
- Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ, 08003, USA
| | - Nahid Turan
- Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ, 08003, USA
| | - Norman P Gerry
- Coriell Institute for Medical Research, 403 Haddon Ave, Camden, NJ, 08003, USA.,Advanced BioMedical Laboratories, 1605 Industrial Hwy, Cinnaminson, NJ, 08007, USA
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16
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Park DS, Eskin I, Kang EY, Gamazon ER, Eng C, Gignoux CR, Galanter JM, Burchard E, Ye CJ, Aschard H, Eskin E, Halperin E, Zaitlen N. An ancestry-based approach for detecting interactions. Genet Epidemiol 2018; 42:49-63. [PMID: 29114909 PMCID: PMC6065511 DOI: 10.1002/gepi.22087] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 09/06/2017] [Accepted: 09/08/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Epistasis and gene-environment interactions are known to contribute significantly to variation of complex phenotypes in model organisms. However, their identification in human association studies remains challenging for myriad reasons. In the case of epistatic interactions, the large number of potential interacting sets of genes presents computational, multiple hypothesis correction, and other statistical power issues. In the case of gene-environment interactions, the lack of consistently measured environmental covariates in most disease studies precludes searching for interactions and creates difficulties for replicating studies. RESULTS In this work, we develop a new statistical approach to address these issues that leverages genetic ancestry, defined as the proportion of ancestry derived from each ancestral population (e.g., the fraction of European/African ancestry in African Americans), in admixed populations. We applied our method to gene expression and methylation data from African American and Latino admixed individuals, respectively, identifying nine interactions that were significant at P<5×10-8. We show that two of the interactions in methylation data replicate, and the remaining six are significantly enriched for low P-values (P<1.8×10-6). CONCLUSION We show that genetic ancestry can be a useful proxy for unknown and unmeasured covariates in the search for interaction effects. These results have important implications for our understanding of the genetic architecture of complex traits.
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Affiliation(s)
- Danny S. Park
- Department of Bioengineering and Therapeutic Sciences. University of California San Francisco. San Francisco, CA
| | - Itamar Eskin
- The Blavatnik School of Computer Science. Tel-Aviv University. Tel Aviv, Israel
| | - Eun Yong Kang
- Department of Computer Science. University of California Los Angeles. Los Angeles, CA
| | - Eric R. Gamazon
- Division of Genetic Medicine, Department of Medicine. Vanderbilt University. Nashville, TN
- Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Celeste Eng
- Department of Medicine. University of California San Francisco. San Francisco, CA
| | - Christopher R. Gignoux
- Department of Bioengineering and Therapeutic Sciences. University of California San Francisco. San Francisco, CA
- Department of Genetics. Stanford University. Palo Alto, CA
| | - Joshua M. Galanter
- Department of Medicine. University of California San Francisco. San Francisco, CA
| | - Esteban Burchard
- Department of Bioengineering and Therapeutic Sciences. University of California San Francisco. San Francisco, CA
- Department of Medicine. University of California San Francisco. San Francisco, CA
| | - Chun J. Ye
- Institute of Human Genetics. University of California San Francisco. San Francisco, CA
| | - Hugues Aschard
- Department of Epidemiology. Harvard School of Public Health. Boston, MA
| | - Eleazar Eskin
- Department of Computer Science. University of California Los Angeles. Los Angeles, CA
| | - Eran Halperin
- The Blavatnik School of Computer Science. Tel-Aviv University. Tel Aviv, Israel
| | - Noah Zaitlen
- Department of Bioengineering and Therapeutic Sciences. University of California San Francisco. San Francisco, CA
- Department of Medicine. University of California San Francisco. San Francisco, CA
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17
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Ceballos FC, Joshi PK, Clark DW, Ramsay M, Wilson JF. Runs of homozygosity: windows into population history and trait architecture. Nat Rev Genet 2018; 19:220-234. [PMID: 29335644 DOI: 10.1038/nrg.2017.109] [Citation(s) in RCA: 472] [Impact Index Per Article: 67.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Long runs of homozygosity (ROH) arise when identical haplotypes are inherited from each parent and thus a long tract of genotypes is homozygous. Cousin marriage or inbreeding gives rise to such autozygosity; however, genome-wide data reveal that ROH are universally common in human genomes even among outbred individuals. The number and length of ROH reflect individual demographic history, while the homozygosity burden can be used to investigate the genetic architecture of complex disease. We discuss how to identify ROH in genome-wide microarray and sequence data, their distribution in human populations and their application to the understanding of inbreeding depression and disease risk.
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Affiliation(s)
- Francisco C Ceballos
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, Johannesburg, South Africa.,Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK
| | - Peter K Joshi
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
| | - David W Clark
- Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
| | - Michèle Ramsay
- Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Parktown 2193, Johannesburg, South Africa.,Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Braamfontein 2000, Johannesburg, South Africa
| | - James F Wilson
- Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.,Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK
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18
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Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure. Psychiatr Genet 2017; 27:54-61. [PMID: 27824727 DOI: 10.1097/ypg.0000000000000159] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson's disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. MATERIALS AND METHODS To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. RESULTS Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. CONCLUSION Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains.
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19
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Blant A, Kwong M, Szpiech ZA, Pemberton TJ. Weighted likelihood inference of genomic autozygosity patterns in dense genotype data. BMC Genomics 2017; 18:928. [PMID: 29191164 PMCID: PMC5709839 DOI: 10.1186/s12864-017-4312-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 11/16/2017] [Indexed: 12/14/2022] Open
Abstract
Background Genomic regions of autozygosity (ROA) arise when an individual is homozygous for haplotypes inherited identical-by-descent from ancestors shared by both parents. Over the past decade, they have gained importance for understanding evolutionary history and the genetic basis of complex diseases and traits. However, methods to infer ROA in dense genotype data have not evolved in step with advances in genome technology that now enable us to rapidly create large high-resolution genotype datasets, limiting our ability to investigate their constituent ROA patterns. Methods We report a weighted likelihood approach for inferring ROA in dense genotype data that accounts for autocorrelation among genotyped positions and the possibilities of unobserved mutation and recombination events, and variability in the confidence of individual genotype calls in whole genome sequence (WGS) data. Results Forward-time genetic simulations under two demographic scenarios that reflect situations where inbreeding and its effect on fitness are of interest suggest this approach is better powered than existing state-of-the-art methods to infer ROA at marker densities consistent with WGS and popular microarray genotyping platforms used in human and non-human studies. Moreover, we present evidence that suggests this approach is able to distinguish ROA arising via consanguinity from ROA arising via endogamy. Using subsets of The 1000 Genomes Project Phase 3 data we show that, relative to WGS, intermediate and long ROA are captured robustly with popular microarray platforms, while detection of short ROA is more variable and improves with marker density. Worldwide ROA patterns inferred from WGS data are found to accord well with those previously reported on the basis of microarray genotype data. Finally, we highlight the potential of this approach to detect genomic regions enriched for autozygosity signals in one group relative to another based upon comparisons of per-individual autozygosity likelihoods instead of inferred ROA frequencies. Conclusions This weighted likelihood ROA inference approach can assist population- and disease-geneticists working with a wide variety of data types and species to explore ROA patterns and to identify genomic regions with differential ROA signals among groups, thereby advancing our understanding of evolutionary history and the role of recessive variation in phenotypic variation and disease. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-4312-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Alexandra Blant
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada
| | - Michelle Kwong
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada
| | - Zachary A Szpiech
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA
| | - Trevor J Pemberton
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
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20
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The distribution and functional relevance analysis of runs of homozygosity (ROHs) in Chinese Han female population. Mol Genet Genomics 2017; 293:197-206. [PMID: 28980070 DOI: 10.1007/s00438-017-1378-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 09/25/2017] [Indexed: 10/18/2022]
Abstract
Extended homozygosity is a genomic region in which the copies inherited from parents are identical, and has obvious inter-individual differences in length and frequency. Runs of homozygosity (ROHs), regarded as a type of structure variations, may have potential capacity in regulating gene transcription. To learn more about the genome-wide distribution of ROH regions in humans and understand the potential roles, this study applied ROH-based approach to quantify and characterize ROHs in 41 Chinese Han female subjects, and test potential associations between ROHs and mRNA expressions by eQTL analysis to ascertain whether ROHs are relevant to gene transcription in peripheral blood mononuclear cells (PBMCs). 10,884 ROH regions were identified in human genome. The average cumulative length of ROH regions was 217,250 ± 20,241 kb. The number of core segments in each chromosome generally matched the total length of corresponding chromosome, i.e., the longer the chromosome, the more the core segments. Genes located in the core regions of ROH were significantly enriched in multiple basic metabolism pathways. A total of 226 cis-eQTLs and 178 trans-eQTLs were identified. The cis-effect size was mainly concentrated at ± 0.5; and the trans-effect size was mainly concentrated at -1.5 and 1.0. Genes with eQTL effects were significantly enriched in functions related to protein binding, cytosol, nucleoplasm, nuclear membrane, protein binding and citrate metabolic process. This study described comprehensive distributions and characteristics of ROH in Han female Chinese, and recognized the significant role of ROH associated with gene transcription in human PBMC.
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21
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Srivastav S, Fatima M, Mondal AC. Important medicinal herbs in Parkinson's disease pharmacotherapy. Biomed Pharmacother 2017; 92:856-863. [PMID: 28599249 DOI: 10.1016/j.biopha.2017.05.137] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 05/10/2017] [Accepted: 05/28/2017] [Indexed: 11/28/2022] Open
Abstract
Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder affecting more than 10 million people worldwide. The characteristic hallmark of PD involves progressive loss of dopaminergic (DA-ergic) neuron in Substantia Nigra pars compacta (SNpc) region of the brain, however, aetiology of the disease still remains unclear. Mitochondrial dysfunction and oxidative insult are considered to be the key culprit. The current therapy available for PD primarily relies on Levodopa that offers the potential of slowing down disease progression to some extent but includes lot of side effects. Any potential drug capable of treating or halting the disease still remains to be identified. It is evident that redox stabilization and replenishment of mitochondrial function seem to be an important therapeutic approach against PD as both are required for optimal neuronal functioning. Enormous research done in this field has shown that some natural and synthetic products exhibit neuroprotective and anti-apoptotic potential by improving mitochondrial function and alleviating oxidative stress. Therefore, the present review aims to discuss some of the important medicinal natural herbs (Bacopa monnieri, Mucuna pruriens, Withania somnifera, Curcuma longa, Gingko Biloba, and Camellia sinensis) in context to their neuroprotective potential and also in the development of novel therapeutic strategies against PD.
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Affiliation(s)
- Saurabh Srivastav
- Laboratory of Cellular & Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Mahino Fatima
- Laboratory of Cellular & Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India
| | - Amal Chandra Mondal
- Laboratory of Cellular & Molecular Neurobiology, School of Life Sciences, Jawaharlal Nehru University, New Delhi, 110067, India.
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22
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Eisfeldt J, Vezzi F, Olason P, Nilsson D, Lindstrand A. TIDDIT, an efficient and comprehensive structural variant caller for massive parallel sequencing data. F1000Res 2017; 6:664. [PMID: 28781756 DOI: 10.12688/f1000research.11168.1] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/05/2017] [Indexed: 01/07/2023] Open
Abstract
Reliable detection of large structural variation ( > 1000 bp) is important in both rare and common genetic disorders. Whole genome sequencing (WGS) is a technology that may be used to identify a large proportion of the genomic structural variants (SVs) in an individual in a single experiment. Even though SV callers have been extensively used in research to detect mutations, the potential usage of SV callers within routine clinical diagnostics is still limited. One well known, but not well-addressed problem is the large number of benign variants and reference errors present in the human genome that further complicates analysis. Even though there is a wide range of SV-callers available, the number of callers that allow detection of the entire spectra of SV at a low computational cost is still relatively limited.
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Affiliation(s)
- Jesper Eisfeldt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.,Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden
| | - Francesco Vezzi
- Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden.,Department of Biochemistry and Biophysics, Stockholm University, 171 21 Stockholm, Sweden
| | - Pall Olason
- Science for Life Laboratory, Dept of Cell and Molecular Biology, Uppsala University, Husargatan 3, Uppsala, SE-752 37, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.,Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
| | - Anna Lindstrand
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
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23
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Eisfeldt J, Vezzi F, Olason P, Nilsson D, Lindstrand A. TIDDIT, an efficient and comprehensive structural variant caller for massive parallel sequencing data. F1000Res 2017; 6:664. [PMID: 28781756 PMCID: PMC5521161 DOI: 10.12688/f1000research.11168.2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2017] [Indexed: 01/25/2023] Open
Abstract
Reliable detection of large structural variation ( > 1000 bp) is important in both rare and common genetic disorders. Whole genome sequencing (WGS) is a technology that may be used to identify a large proportion of the genomic structural variants (SVs) in an individual in a single experiment. Even though SV callers have been extensively used in research to detect mutations, the potential usage of SV callers within routine clinical diagnostics is still limited. One well known, but not well-addressed problem is the large number of benign variants and reference errors present in the human genome that further complicates analysis. Even though there is a wide range of SV-callers available, the number of callers that allow detection of the entire spectra of SV at a low computational cost is still relatively limited.
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Affiliation(s)
- Jesper Eisfeldt
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.,Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden
| | - Francesco Vezzi
- Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden.,Department of Biochemistry and Biophysics, Stockholm University, 171 21 Stockholm, Sweden
| | - Pall Olason
- Science for Life Laboratory, Dept of Cell and Molecular Biology, Uppsala University, Husargatan 3, Uppsala, SE-752 37, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.,Science for Life Laboratory, Karolinska Institutet Science Park, 171 21 Solna, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
| | - Anna Lindstrand
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
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Joesch-Cohen LM, Glusman G. Differences between the genomes of lymphoblastoid cell lines and blood-derived samples. ADVANCES IN GENOMICS AND GENETICS 2017; 7:1-9. [PMID: 28736497 PMCID: PMC5520659 DOI: 10.2147/agg.s128824] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Lymphoblastoid cell lines (LCLs) represent a convenient research tool for expanding the amount of biologic material available from an individual. LCLs are commonly used as reference materials, most notably from the Genome in a Bottle Consortium. However, the question remains how faithfully LCL-derived genome assemblies represent the germline genome of the donor individual as compared to the genome assemblies derived from peripheral blood mononuclear cells. We present an in-depth comparison of a large collection of LCL- and peripheral blood mononuclear cell-derived genomes in terms of distributions of coverage and copy number alterations. We found significant differences in the depth of coverage and copy number calls, which may be driven by differential replication timing. Importantly, these copy number changes preferentially affect regions closer to genes and with higher GC content. This suggests that genomic studies based on LCLs may display locus-specific biases, and that conclusions based on analysis of depth of coverage and copy number variation may require further scrutiny.
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25
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Gallo A, Vella S, Miele M, Timoneri F, Di Bella M, Bosi S, Sciveres M, Conaldi PG. Global profiling of viral and cellular non-coding RNAs in Epstein-Barr virus-induced lymphoblastoid cell lines and released exosome cargos. Cancer Lett 2016; 388:334-343. [PMID: 27956246 DOI: 10.1016/j.canlet.2016.12.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 12/01/2016] [Accepted: 12/02/2016] [Indexed: 01/01/2023]
Abstract
The human EBV-transformed lymphoblastoid cell line (LCL), obtained by infecting peripheral blood monocular cells with Epstein-Barr Virus, has been extensively used for human genetic, pharmacogenomic, and immunologic studies. Recently, the role of exosomes has also been indicated as crucial in the crosstalk between EBV and the host microenvironment. Because the role that the LCL and LCL exosomal cargo might play in maintaining persistent infection, and since little is known regarding the non-coding RNAs of LCL, the aim of our work was the comprehensive characterization of this class of RNA, cellular and viral miRNAs, and cellular lncRNAs, in LCL compared with PBMC derived from the same donors. In this study, we have demonstrated, for the first time, that all the viral miRNAs expressed by LCL are also packaged in the exosomes, and we found that two miRNAs, ebv-miR-BART3 and ebv-miR-BHRF1-1, are more abundant in the exosomes, suggesting a microvescicular viral microRNA transfer. In addition, lncRNA profiling revealed that LCLs were enriched in lncRNA H19 and H19 antisense, and released these through exosomes, suggesting a leading role in the regulation of the tumor microenvironment.
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Affiliation(s)
- Alessia Gallo
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Italy.
| | - Serena Vella
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Italy
| | | | | | | | | | - Marco Sciveres
- Pediatric Hepatology and Liver Transplantation, IRCCS ISMETT, University of Pittsburgh Medical Center, Palermo, Italy
| | - Pier Giulio Conaldi
- Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Italy; Fondazione Ri.MED, Italy
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26
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CONSANGUINITY BY RANDOM ISONYMY AND SOCIOECONOMIC DEVELOPMENT IN ARGENTINA: A POPULATION STUDY. J Biosoc Sci 2016; 49:322-333. [PMID: 27725003 DOI: 10.1017/s0021932016000444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
In human populations various flexible, labile and interdependent structures (genetic, demographic, socioeconomic) co-exist, each of which can be organized in an hierarchical order corresponding to administrative entities. The relationship between consanguinity, as estimated by random isonymy (F ST), and socioeconomic conditions was analysed at different levels of political and administrative organization in Argentina. From the surnames of 22,666,139 voters from the 2001 electoral roll, F ST was estimated for 510 Argentinian departments. Using a principal component analysis, a Socio-Demographic and Economic Indicator (SDEI), summarizing the effect of 22 socioeconomic and demographic variables at the departmental level, was computed. The relationship between departmental F ST and SDEI values was analysed for the whole nation and within regions using multiple regression analysis. The F ST presented a clinal distribution with the highest values in the north and west of the country, while SDEI expressed the opposite behaviour. A negative and significant correlation was observed between F ST and SDEI, accounting for 46% of the variation in consanguinity in Argentina. The strongest correlations of F ST with SDEI were observed in the Central, Patagonia and Cuyo regions, i.e. those with the highest values of SDEI and lowest values of F ST.
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27
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McCarthy NS, Allan SM, Chandler D, Jablensky A, Morar B. Integrity of genome-wide genotype data from low passage lymphoblastoid cell lines. GENOMICS DATA 2016; 9:18-21. [PMID: 27330997 PMCID: PMC4909818 DOI: 10.1016/j.gdata.2016.05.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 05/09/2016] [Accepted: 05/09/2016] [Indexed: 01/08/2023]
Abstract
We compared genotype data from the HumanExomeCore Array in peripheral blood mononuclear cells and low passage lymphoblastoid cell lines from the same 24 individuals to test for genotypic errors caused by the Epstein–Barr Virus transformation process. Genotype concordance across the 24 comparisons was 99.57% for unfiltered genotype data, and 99.63% following standard genotype quality control filters. Mendelian error rates and levels of heterozygosity were not significantly different between lymphoblastoid cell lines and their parent peripheral blood mononuclear cells. These results show that at low passage numbers, genotype discrepancies are minimal even before stringent quality control, and extend current evidence qualifying the use of low-passage lymphoblastoid cell lines as a reliable DNA source for genotype analysis.
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Affiliation(s)
- Nina S McCarthy
- Centre for the Genetic Origins of Health and Disease, The University of Western Australia, Perth, Australia; Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Australia; Cooperative Research Centre for Mental Health, Carlton South, Victoria, Australia
| | - Spencer M Allan
- Centre for the Genetic Origins of Health and Disease, The University of Western Australia, Perth, Australia
| | - David Chandler
- Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Australia
| | - Assen Jablensky
- Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Australia; Cooperative Research Centre for Mental Health, Carlton South, Victoria, Australia
| | - Bharti Morar
- Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Australia; Cooperative Research Centre for Mental Health, Carlton South, Victoria, Australia; Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia
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28
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Saadati HR, Wittig M, Helbig I, Häsler R, Anderson CA, Mathew CG, Kupcinskas L, Parkes M, Karlsen TH, Rosenstiel P, Schreiber S, Franke A. Genome-wide rare copy number variation screening in ulcerative colitis identifies potential susceptibility loci. BMC MEDICAL GENETICS 2016; 17:26. [PMID: 27037036 PMCID: PMC4818401 DOI: 10.1186/s12881-016-0289-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 03/23/2016] [Indexed: 12/30/2022]
Abstract
Background Ulcerative colitis (UC), a complex polygenic disorder, is one of the main subphenotypes of inflammatory bowel disease. A comprehensive dissection of the genetic etiology of UC needs to assess the contribution of rare genetic variants including copy number variations (CNVs) to disease risk. In this study, we performed a multi-step genome-wide case-control analysis to interrogate the presence of disease-relevant rare copy number variants. Methods One thousand one hundred twenty-one German UC patients and 1770 healthy controls were initially screened for rare deletions and duplications employing SNP-array data. Quantitative PCR and high density custom array-CGH were used for validation of identified CNVs and fine mapping. Two main follow-up panels consisted of an independent cohort of 451 cases and 1274 controls, in which CNVs were assayed through quantitative PCR, and a British cohort of 2396 cases versus 4886 controls with CNV genotypes based on array data. Additional sample sets were assessed for targeted and in silico replication. Results Twenty-four rare copy number variants (14 deletions and 10 duplications), overrepresented in UC patients were identified in the initial screening panel. Follow-up of these CNV regions in four independent case-control series as well as an additional public in silico control group (totaling 4439 UC patients and 15,961 healthy controls) revealed three copy number variants enriched in UC patients; a 15.8 kb deletion upstream of ABCC4 and CLDN10 at13q32.1 (0.43 % cases, 0.11 % controls), a 119 kb duplication at 7p22.1, overlapping RNF216, ZNF815, OCM and CCZ1 (0.13 % cases, 0.01 % controls) and a 134 kb large duplication upstream of the KCNK9 gene at 8q24.3 (0.22 % carriers among cases, 0.03 % carriers among controls). The trend of association with UC was present after the P-values were corrected for combining data from different subpopulations. Break-point mapping of the deleted region suggested non-allelic homologous recombination as the mechanism underlying its formation. Conclusion Our study presents a pragmatic approach for effective rare CNV screening of SNP-array data sets and implicates the potential contribution of rare structural variants in the pathogenesis of UC. Electronic supplementary material The online version of this article (doi:10.1186/s12881-016-0289-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hamid Reza Saadati
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Michael Wittig
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Ingo Helbig
- Department of Neuropediatrics, University Clinic Schleswig-Holstein, Campus Kiel, Arnold-Heller-Strasse 3, Building 9, 24105, Kiel, Germany
| | - Robert Häsler
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Carl A Anderson
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
| | - Christopher G Mathew
- Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK
| | - Limas Kupcinskas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Mickeviciaus 9, Kaunas, LT, 44307, Lithuania
| | - Miles Parkes
- Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 2QQ, UK
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital, Rikshospitalet, 0027, Oslo, Norway
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.,Department of Internal Medicine, University Hospital Schleswig-Holstein, Schittenhelmstraße 12, 24105, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Schittenhelmstr. 12, 24105, Kiel, Germany.
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Bodea CA, Middleton FA, Melhem NM, Klei L, Song Y, Tiobech J, Marumoto P, Yano V, Faraone SV, Roeder K, Myles-Worsley M, Devlin B, Byerley W. Analysis of Shared Haplotypes amongst Palauans Maps Loci for Psychotic Disorders to 4q28 and 5q23-q31. Complex Psychiatry 2016; 2:173-184. [DOI: 10.1159/000450726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 08/19/2016] [Indexed: 11/19/2022] Open
Abstract
To localize genetic variation affecting risk for psychotic disorders in the population of Palau, we genotyped DNA samples from 203 Palauan individuals diagnosed with psychotic disorders, broadly defined, and 125 control subjects using a genome-wide single nucleotide polymorphism array. Palau has unique features advantageous for this study: due to its population history, Palauans are substantially interrelated; affected individuals often, but not always, cluster in families; and we have essentially complete ascertainment of affected individuals. To localize risk variants to genomic regions, we evaluated long-shared haplotypes, ≥10 Mb, identifying clusters of affected individuals who share such haplotypes. This extensive sharing, typically identical by descent, was significantly greater in cases than population controls, even after controlling for relatedness. Several regions of the genome exhibited substantial excess of shared haplotypes for affected individuals, including 3p21, 3p12, 4q28, and 5q23-q31. Two of these regions, 4q28 and 5q23-q31, showed significant linkage by traditional LOD score analysis and could harbor variants of more sizeable risk for psychosis or a multiplicity of risk variants. The pattern of haplotype sharing in 4q28 highlights <i>PCDH10</i>, encoding a cadherin-related neuronal receptor, as possibly involved in risk.
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30
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Sud A, Cooke R, Swerdlow AJ, Houlston RS. Genome-wide homozygosity signature and risk of Hodgkin lymphoma. Sci Rep 2015; 5:14315. [PMID: 26391888 PMCID: PMC4585760 DOI: 10.1038/srep14315] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 08/25/2015] [Indexed: 12/11/2022] Open
Abstract
Recent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing Hodgkin lymphoma (HL) we analysed 589 HL cases and 5,199 controls genotyped for 484,072 tag single nucleotide polymorphisms (SNPs). Across the genome the cumulative distribution of ROH was not significantly different between cases and controls. Seven ROH at 4q22.3, 4q32.2, 7p12.3-14.1, 7p22.2, 10p11.22-23, 19q13.12-2 and 19p13.2 were associated with HL risk at P < 0.01. Intriguingly 4q22.3 harbours an ROH to which the nuclear factor NF-kappa-B p105 subunit (NFKB1) maps (P = 0.002). The ROH at 19q13.12-2 has previously been implicated in B-cell precursor acute lymphoblastic leukaemia. Aside from these observations which require validation, it is unlikely that levels of measured homozygosity caused by autozygosity, uniparental isodisomy or hemizygosity play a major role in defining HL risk in predominantly outbred populations.
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Affiliation(s)
- Amit Sud
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Rosie Cooke
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
| | - Anthony J. Swerdlow
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
- Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
| | - Richard S. Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK
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31
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Somatic mosaicism for copy-neutral loss of heterozygosity and DNA copy number variations in the human genome. BMC Genomics 2015; 16:703. [PMID: 26376747 PMCID: PMC4573927 DOI: 10.1186/s12864-015-1916-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Accepted: 09/09/2015] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Somatic mosaicism denotes the presence of genetically distinct populations of somatic cells in one individual who has developed from a single fertilised oocyte. Mosaicism may result from a mutation that occurs during postzygotic development and is propagated to only a subset of the adult cells. Our aim was to investigate both somatic mosaicism for copy-neutral loss of heterozygosity (cn-LOH) events and DNA copy number variations (CNVs) in fully differentiated tissues. RESULTS We studied panels of tissue samples (11-12 tissues per individual) from four autopsy subjects using high-resolution Illumina HumanOmniExpress-12 BeadChips to reveal the presence of possible intra-individual tissue-specific cn-LOH and CNV patterns. We detected five mosaic cn-LOH regions >5 Mb in some tissue samples in three out of four individuals. We also detected three CNVs that affected only a portion of the tissues studied in one out of four individuals. These three somatic CNVs range from 123 to 796 kb and are also found in the general population. An attempt was made to explain the succession of genomic events that led to the observed somatic genetic mosaicism under the assumption that the specific mosaic patterns of CNV and cn-LOH changes reflect their formation during the postzygotic embryonic development of germinal layers and organ systems. CONCLUSIONS Our results give further support to the idea that somatic mosaicism for CNVs, and also cn-LOHs, is a common phenomenon in phenotypically normal humans. Thus, the examination of only a single tissue might not provide enough information to diagnose potentially deleterious CNVs within an individual. During routine CNV and cn-LOH analysis, DNA derived from a buccal swab can be used in addition to blood DNA to get information about the CNV/cn-LOH content in tissues of both mesodermal and ectodermal origin. Currently, the real frequency and possible phenotypic consequences of both CNVs and cn-LOHs that display somatic mosaicism remain largely unknown. To answer these questions, future studies should involve larger cohorts of individuals and a range of tissues.
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López S, García I, Smith I, Sevilla A, Izagirre N, de la Rúa C, Alonso S. Discovery of copy number variants by multiplex amplifiable probe hybridization (MAPH) in candidate pigmentation genes. Ann Hum Biol 2015; 42:485-93. [DOI: 10.3109/03014460.2014.965202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Gennarino VA, Alcott CE, Chen CA, Chaudhury A, Gillentine MA, Rosenfeld JA, Parikh S, Wheless JW, Roeder ER, Horovitz DDG, Roney EK, Smith JL, Cheung SW, Li W, Neilson JR, Schaaf CP, Zoghbi HY. NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation. eLife 2015; 4. [PMID: 26312503 PMCID: PMC4586391 DOI: 10.7554/elife.10782] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Accepted: 08/26/2015] [Indexed: 01/27/2023] Open
Abstract
The brain is sensitive to the dose of MeCP2 such that small fluctuations in protein quantity lead to neuropsychiatric disease. Despite the importance of MeCP2 levels to brain function, little is known about its regulation. In this study, we report eleven individuals with neuropsychiatric disease and copy-number variations spanning NUDT21, which encodes a subunit of pre-mRNA cleavage factor Im. Investigations of MECP2 mRNA and protein abundance in patient-derived lymphoblastoid cells from one NUDT21 deletion and three duplication cases show that NUDT21 regulates MeCP2 protein quantity. Elevated NUDT21 increases usage of the distal polyadenylation site in the MECP2 3′ UTR, resulting in an enrichment of inefficiently translated long mRNA isoforms. Furthermore, normalization of NUDT21 via siRNA-mediated knockdown in duplication patient lymphoblasts restores MeCP2 to normal levels. Ultimately, we identify NUDT21 as a novel candidate for intellectual disability and neuropsychiatric disease, and elucidate a mechanism of pathogenesis by MeCP2 dysregulation via altered alternative polyadenylation. DOI:http://dx.doi.org/10.7554/eLife.10782.001 The X-chromosome carries a number of genes that are involved in a child's intellectual development. One of these genes encodes a protein called MeCP2, which is important for brain function after birth. Mutations in the MECP2 gene cause a disorder known as Rett syndrome. At around 18 months of age, affected children begin to lose the cognitive and motor skills that they had previously acquired. Individuals with extra copies of this gene also show cognitive impairments. For both diseases, individuals with levels of the MeCP2 protein that are the most different from those found in healthy individuals also show the most severe symptoms. To produce the protein that is encoded by a particular gene, enzymes inside the cell must first make a copy of that gene using a molecule called messenger ribonucleic acid (or mRNA). This mRNA is then used as a template to assemble the protein itself. In the case of MECP2, two different mRNA templates are produced: a long version and a short version. A gene called NUDT21 makes a protein that regulates whether the long or short version of MECP2 mRNA is made. Gennarino, Alcott et al. have now discovered that people with too many, or too few, copies of the NUDT21 gene have intellectual disabilities and altered levels of MeCP2 protein. Specifically, individuals with extra copies of NUDT21—and thus higher levels of the corresponding protein—produce more of the long MECP2 mRNA. The production of proteins from this long mRNA is less efficient than from the short mRNA; therefore, these individuals have lower levels of MeCP2 protein. The opposite is true for individuals who lack a copy of the NUDT21 gene. To confirm these data, Gennarino, Alcott et al. grew cells in the laboratory from patients with extra copies of the NUDT21 gene and found that reducing the production of its protein returned the levels of the MeCP2 protein back to normal. These findings show that alterations in the NUDT21 gene cause changes in the level of MeCP2 protein in cells and leads to neuropsychiatric diseases. DOI:http://dx.doi.org/10.7554/eLife.10782.002
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Affiliation(s)
- Vincenzo A Gennarino
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Callison E Alcott
- Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States
| | - Chun-An Chen
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Arindam Chaudhury
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
| | - Madelyn A Gillentine
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Sumit Parikh
- Center for Child Neurology, Cleveland Clinic Children's Hospital, Cleveland, United States
| | - James W Wheless
- Department of Pediatric Neurology, Neuroscience Institute and Tuberous Sclerosis Clinic, Le Bonheur Children's Hospital, University of Tennessee Health Science Center, Memphis, United States
| | - Elizabeth R Roeder
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Dafne D G Horovitz
- Depto de Genetica Medica, Instituto Nacional de Saude da Mulher, da Criança e do Adolescente Fernandes Figueira, Rio de Janeiro, Brazil
| | - Erin K Roney
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Janice L Smith
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Sau W Cheung
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Wei Li
- Division of Biostatistics, Dan L Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
| | - Joel R Neilson
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States
| | - Christian P Schaaf
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
| | - Huda Y Zoghbi
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
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Haplotype phasing and inheritance of copy number variants in nuclear families. PLoS One 2015; 10:e0122713. [PMID: 25853576 PMCID: PMC4390228 DOI: 10.1371/journal.pone.0122713] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 02/12/2015] [Indexed: 11/19/2022] Open
Abstract
DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.
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Khankhanian P, Din L, Caillier SJ, Gourraud PA, Baranzini SE. SNP imputation bias reduces effect size determination. Front Genet 2015; 6:30. [PMID: 25709616 PMCID: PMC4321633 DOI: 10.3389/fgene.2015.00030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 01/21/2015] [Indexed: 12/14/2022] Open
Abstract
Imputation is a commonly used technique that exploits linkage disequilibrium to infer missing genotypes in genetic datasets, using a well-characterized reference population. While there is agreement that the reference population has to match the ethnicity of the query dataset, it is common practice to use the same reference to impute genotypes for a wide variety of phenotypes. We hypothesized that using a reference composed of samples with a different phenotype than the query dataset would introduce imputation bias. To test this hypothesis we used GWAS datasets from Amyotrophic Lateral Sclerosis (ALS), Parkinson Disease (PD), and Crohn's Disease (CD). First, we masked and then performed imputation of 100 disease-associated markers and 100 non-associated markers from each study. Two references for imputation were used in parallel: one consisting of healthy controls and another consisting of patients with the same disease. We assessed the discordance (imprecision) and bias (inaccuracy) of imputation by comparing predicted genotypes to those assayed by SNP-chip. We also assessed the bias on the observed effect size when the predicted genotypes were used in a GWAS study. When healthy controls were used as reference for imputation, a significant bias was observed, particularly in the disease-associated markers. Using cases as reference significantly attenuated this bias. For nearly all markers, the direction of the bias favored the non-risk allele. In GWAS studies of the three diseases (with healthy reference controls from the 1000 genomes as reference), the mean OR for disease-associated markers obtained by imputation was lower than that obtained using original assayed genotypes. We found that the bias is inherent to imputation as using different methods did not alter the results. In conclusion, imputation is a powerful method to predict genotypes and estimate genetic risk for GWAS. However, a careful choice of reference population is needed to minimize biases inherent to this approach.
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Affiliation(s)
- Pouya Khankhanian
- Department of Neurology, University of California San Francisco San Francisco, CA, USA
| | - Lennox Din
- Department of Neurology, University of California San Francisco San Francisco, CA, USA
| | - Stacy J Caillier
- Department of Neurology, University of California San Francisco San Francisco, CA, USA
| | | | - Sergio E Baranzini
- Department of Neurology, University of California San Francisco San Francisco, CA, USA
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Johnson JO, Stevanin G, van de Leemput J, Hernandez DG, Arepalli S, Forlani S, Zonozi R, Gibbs JR, Brice A, Durr A, Singleton AB. A 7.5-Mb duplication at chromosome 11q21-11q22.3 is associated with a novel spastic ataxia syndrome. Mov Disord 2014; 30:262-6. [PMID: 25545641 DOI: 10.1002/mds.26059] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 07/28/2014] [Accepted: 08/25/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The autosomal dominant spinocerebellar ataxias are most commonly caused by nucleotide repeat expansions followed by base-pair changes in functionally important genes. Structural variation has recently been shown to underlie spinocerebellar ataxia types 15 and 20. METHODS We applied single-nucleotide polymorphism (SNP) genotyping to determine whether structural variation causes spinocerebellar ataxia in a family from France. RESULTS We identified an approximately 7.5-megabasepair duplication on chromosome 11q21-11q22.3 that segregates with disease. This duplication contains an estimated 44 genes. Duplications at this locus were not found in control individuals. CONCLUSIONS We have identified a new spastic ataxia syndrome caused by a genomic duplication, which we have denoted as spinocerebellar ataxia type 39. Finding additional families with this phenotype will be important to identify the genetic lesion underlying disease.
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Affiliation(s)
- Janel O Johnson
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London, Queen Square, London, UK
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Melhem NM, Lu C, Dresbold C, Middleton FA, Klei L, Wood S, Faraone SV, Vinogradov S, Tiobech J, Yano V, Roeder K, Byerley W, Myles-Worsley M, Devlin B. Characterizing runs of homozygosity and their impact on risk for psychosis in a population isolate. Am J Med Genet B Neuropsychiatr Genet 2014; 165B:521-30. [PMID: 24980794 PMCID: PMC5058445 DOI: 10.1002/ajmg.b.32255] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 06/04/2014] [Indexed: 11/12/2022]
Abstract
An increased abundance of runs of homozygosity (ROH) has been associated with risk for various diseases, including schizophrenia. Here we investigate the characteristics of ROH in Palau, an Oceanic population, evaluating whether these characteristics are related to risk for psychotic disorders and the nature of this association. To accomplish these aims we evaluate a sample of 203 cases with schizophrenia and related psychotic disorders-representing almost complete ascertainment of affected individuals in the population-and contrast their ROH to that of 125 subjects chosen to function as controls. While Palauan diagnosed with psychotic disorders tend to have slightly more ROH regions than controls, the distinguishing features are that they have longer ROH regions, greater total length of ROH, and their ROH tends to co-occur more often at the same locus. The nature of the sample allows us to investigate whether rare, highly penetrant recessive variants generate such case-control differences in ROH. Neither rare, highly penetrant recessive variants nor individual common variants of large effect account for a substantial proportion of risk for psychosis in Palau. These results suggest a more nuanced model for risk is required to explain patterns of ROH for this population.
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Affiliation(s)
- Nadine M. Melhem
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Cong Lu
- Department of Statistics, Carnegie Mellon University, Pittsburgh, PA
| | - Cara Dresbold
- Department of Human Genetics, University of Pittsburgh
| | | | | | - Shawn Wood
- University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Stephen V Faraone
- Department of Psychiatry, SUNY Upstate Medical University; Syracuse NY
| | | | | | - Victor Yano
- Palauan Ministry of Health, Republic of Palau
| | - Kathryn Roeder
- Department of Statistics, Carnegie Mellon University, Pittsburgh, PA
| | - William Byerley
- Department of Psychiatry, University of California San Francisco
| | | | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Kara E, Kiely AP, Proukakis C, Giffin N, Love S, Hehir J, Rantell K, Pandraud A, Hernandez DG, Nacheva E, Pittman AM, Nalls MA, Singleton AB, Revesz T, Bhatia KP, Quinn N, Hardy J, Holton JL, Houlden H. A 6.4 Mb duplication of the α-synuclein locus causing frontotemporal dementia and Parkinsonism: phenotype-genotype correlations. JAMA Neurol 2014; 71:1162-71. [PMID: 25003242 PMCID: PMC4362700 DOI: 10.1001/jamaneurol.2014.994] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IMPORTANCE α-Synuclein (SNCA) locus duplications are associated with variable clinical features and reduced penetrance but the reasons underlying this variability are unknown. OBJECTIVES To report a novel family carrying a heterozygous 6.4 Mb duplication of the SNCA locus with an atypical clinical presentation strongly reminiscent of frontotemporal dementia and late-onset pallidopyramidal syndromes and study phenotype-genotype correlations in SNCA locus duplications. DESIGN, SETTING, AND PARTICIPANTS We report the clinical and neuropathologic features of a family carrying a 6.4 Mb duplication of the SNCA locus. To identify candidate disease modifiers, we completed a genetic analysis of the family and conducted statistical analysis on previously published cases carrying SNCA locus duplications using regression modeling with robust standard errors to account for clustering at the family level. MAIN OUTCOMES AND MEASURES We assessed whether length of the SNCA locus duplication influences disease penetrance and severity and whether extraduplication factors have a disease-modifying role. RESULTS We identified a large 6.4 Mb duplication of the SNCA locus in this family. Neuropathological analysis showed extensive α-synuclein pathology with minimal phospho-tau pathology. Genetic analysis showed an increased burden of Parkinson disease-related risk factors and the disease-predisposing H1/H1 microtubule-associated protein tau haplotype. Statistical analysis of previously published cases suggested there is a trend toward increasing disease severity and disease penetrance with increasing duplication size. The corresponding odds ratios from the univariable analyses were 1.17 (95% CI, 0.81-1.68) and 1.34 (95% CI, 0.78-2.31), respectively. Sex was significantly associated with both disease risk and severity; men compared with women had increased disease risk and severity and the corresponding odds ratios from the univariable analyses were 8.36 (95% CI, 1.97-35.42) and 5.55 (95% CI, 1.39-22.22), respectively. CONCLUSIONS AND RELEVANCE These findings further expand the phenotypic spectrum of SNCA locus duplications. Increased dosage of genes located within the duplicated region probably cannot increase disease risk and disease severity without the contribution of additional risk factors. Identification of disease modifiers accounting for the substantial phenotypic heterogeneity of patients with SNCA locus duplications could provide insight into molecular events involved in α-synuclein aggregation.
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Affiliation(s)
- Eleanna Kara
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Aoife P Kiely
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- The Queen Square Brain Bank, UCL Institute of Neurology, London, UK
| | - Christos Proukakis
- Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK
| | - Nicola Giffin
- Department of Neurology, Frenchay Hospital, Bristol, UK
| | - Seth Love
- Department of Neuropathology, Frenchay Hospital, Bristol, UK
| | - Jason Hehir
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Khadija Rantell
- Biomedical Research Centre, UCL, London, UK
- Education Unit, UCL Institute of Neurology, Queen Square, London, UK
| | - Amelie Pandraud
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Dena G Hernandez
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- Laboratory of Neurogenetics, NIA, NIH, Bethesda, USA
| | | | - Alan M Pittman
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Mike A Nalls
- Laboratory of Neurogenetics, NIA, NIH, Bethesda, USA
| | | | - Tamas Revesz
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- The Queen Square Brain Bank, UCL Institute of Neurology, London, UK
| | - Kailash P Bhatia
- Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
| | - Niall Quinn
- Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
| | - John Hardy
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
| | - Janice L Holton
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- The Queen Square Brain Bank, UCL Institute of Neurology, London, UK
| | - Henry Houlden
- Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK
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39
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Dipierri J, Rodríguez-Larralde A, Barrai I, Camelo JL, Redomero EG, Rodríguez CA, Ramallo V, Bronberg R, Alfaro E. Random inbreeding, isonymy, and population isolates in Argentina. J Community Genet 2014; 5:241-8. [PMID: 24500769 PMCID: PMC4059845 DOI: 10.1007/s12687-013-0181-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 12/29/2013] [Indexed: 12/20/2022] Open
Abstract
Population isolates are an important tool in identifying and mapping genes of Mendelian diseases and complex traits. The geographical identification of isolates represents a priority from a genetic and health care standpoint. The purpose of this study is to analyze the spatial distribution of consanguinity by random isonymy (F ST) in Argentina and its relationship with the isolates previously identified in the country. F ST was estimated from the surname distribution of 22.6 million electors registered for the year 2001 in the 24 provinces, 5 geographical regions, and 510 departments of the country. Statistically significant spatial clustering of F ST was determined using the SaTScan V5.1 software. F ST exhibited a marked regional and departamental variation, showing the highest values towards the North and West of Argentina. The clusters of high consanguinity by random isonymy followed the same distribution. Recognized Argentinean genetic isolates are mainly localized at the north of the country, in clusters of high inbreeding. Given the availability of listings of surnames in high-capacity storage devices for different countries, estimating F ST from them can provide information on inbreeding for all levels of administrative subdivisions, to be used as a demographic variable for the identification of isolates within the country for public health purposes.
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Affiliation(s)
- José Dipierri
- Instituto de Biología de la Altura, Universidad Nacional de Jujuy, Avda. Bolivia 1661, 4600, San Salvador de Jujuy, Argentina,
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Abstract
Copy number variants (CNVs) are deletions or duplications of DNA. CNVs have been increasingly recognized as an important source of both normal genetic variation and pathogenic mutation. Technologies for genome-wide discovery of CNVs facilitate studies of large cohorts of patients and controls to identify CNVs that cause increased risk for disease. Over the past 5 years, studies of patients with epilepsy confirm that both recurrent and non-recurrent CNVs are an important source of mutation for patients with various forms of epilepsy. Here, we will review the latest findings and explore the clinical implications.
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Affiliation(s)
- Heather C. Mefford
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, RR349A, Box 356320, Seattle, WA USA
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41
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Heron EA, Cormican P, Donohoe G, O'Neill FA, Kendler KS, Riley BP, Gill M, Corvin AP, Morris DW. No evidence that runs of homozygosity are associated with schizophrenia in an Irish genome-wide association dataset. Schizophr Res 2014; 154:79-82. [PMID: 24560374 PMCID: PMC4034753 DOI: 10.1016/j.schres.2014.01.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 01/10/2014] [Accepted: 01/27/2014] [Indexed: 11/22/2022]
Abstract
Runs of homozygosity (ROH), regions of the genome containing many consecutive homozygous SNPs, may represent two copies of a haplotype inherited from a common ancestor. A rare variant on this haplotype could thus be present in a homozygous and potentially recessive state. To detect rare risk variants for schizophrenia, we performed an ROH analysis in a homogeneous Irish genome wide association study (GWAS) dataset consisting of 1606 cases and 1794 controls. There was no genome-wide excess of ROH in cases compared to controls (p=0.7986). No consensus ROH at individual loci showed association with schizophrenia after genome-wide correction.
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Affiliation(s)
- Elizabeth A Heron
- Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
| | - Paul Cormican
- Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
| | - Gary Donohoe
- Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
| | - Francis A O'Neill
- Department of Psychiatry, Queen's University, Belfast, BT7 1NN, Northern Ireland, United Kingdom.
| | - Kenneth S Kendler
- Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States; Department of Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States.
| | - Brien P Riley
- Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States; Department of Human Genetics, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States.
| | - Michael Gill
- Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
| | - Aiden P Corvin
- Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
| | - Derek W Morris
- Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, St. James's Hospital, Dublin 8, Ireland.
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Talwar P, Silla Y, Grover S, Gupta M, Agarwal R, Kushwaha S, Kukreti R. Genomic convergence and network analysis approach to identify candidate genes in Alzheimer's disease. BMC Genomics 2014; 15:199. [PMID: 24628925 PMCID: PMC4028079 DOI: 10.1186/1471-2164-15-199] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 02/21/2014] [Indexed: 01/28/2023] Open
Abstract
Background Alzheimer’s disease (AD) is one of the leading genetically complex and heterogeneous disorder that is influenced by both genetic and environmental factors. The underlying risk factors remain largely unclear for this heterogeneous disorder. In recent years, high throughput methodologies, such as genome-wide linkage analysis (GWL), genome-wide association (GWA) studies, and genome-wide expression profiling (GWE), have led to the identification of several candidate genes associated with AD. However, due to lack of consistency within their findings, an integrative approach is warranted. Here, we have designed a rank based gene prioritization approach involving convergent analysis of multi-dimensional data and protein-protein interaction (PPI) network modelling. Results Our approach employs integration of three different AD datasets- GWL,GWA and GWE to identify overlapping candidate genes ranked using a novel cumulative rank score (SR) based method followed by prioritization using clusters derived from PPI network. SR for each gene is calculated by addition of rank assigned to individual gene based on either p value or score in three datasets. This analysis yielded 108 plausible AD genes. Network modelling by creating PPI using proteins encoded by these genes and their direct interactors resulted in a layered network of 640 proteins. Clustering of these proteins further helped us in identifying 6 significant clusters with 7 proteins (EGFR, ACTB, CDC2, IRAK1, APOE, ABCA1 and AMPH) forming the central hub nodes. Functional annotation of 108 genes revealed their role in several biological activities such as neurogenesis, regulation of MAP kinase activity, response to calcium ion, endocytosis paralleling the AD specific attributes. Finally, 3 potential biochemical biomarkers were found from the overlap of 108 AD proteins with proteins from CSF and plasma proteome. EGFR and ACTB were found to be the two most significant AD risk genes. Conclusions With the assumption that common genetic signals obtained from different methodological platforms might serve as robust AD risk markers than candidates identified using single dimension approach, here we demonstrated an integrated genomic convergence approach for disease candidate gene prioritization from heterogeneous data sources linked to AD. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-199) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | | | | | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi 110 007, India.
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Chakrabarty S, D'Souza RR, Kabekkodu SP, Gopinath PM, Rossignol R, Satyamoorthy K. Upregulation of TFAM and mitochondria copy number in human lymphoblastoid cells. Mitochondrion 2014; 15:52-58. [PMID: 24462998 DOI: 10.1016/j.mito.2014.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 01/10/2014] [Accepted: 01/15/2014] [Indexed: 12/12/2022]
Abstract
Mitochondria are central to several physiological and pathological conditions in humans. In the present study, we performed copy number analysis of nuclear encoded mitochondrial genes, in peripheral blood mononuclear cells (PBMCs) and its representative lymphoblastoid cells (LCLs). We have observed hyper diploid copies of mitochondrial transcription factor A (TFAM) gene in the LCLs along with increased mtDNA copy number, mitochondrial mass, intracellular ROS and mitochondrial membrane potential, suggesting elevated mitochondrial biogenesis in LCLs. Gene expression analysis confirmed TFAM over-expression in LCLs when compared to PBMC. Based on our observation, we suggest that increased copy number of TFAM gene upregulates its expression, increases mtDNA copy numbers and protects it from oxidative stress induced damage in the transformed LCLs.
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Affiliation(s)
- Sanjiban Chakrabarty
- Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal 576104, Karnataka State, India.
| | - Reena Reshma D'Souza
- Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal 576104, Karnataka State, India.
| | - Shama Prasada Kabekkodu
- Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal 576104, Karnataka State, India.
| | - Puthiya M Gopinath
- Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal 576104, Karnataka State, India.
| | - Rodrigue Rossignol
- Institut National de la Santé et de la Recherché Médicale (INSERM), U688 Physiopathologie Mitochondriale, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France.
| | - Kapaettu Satyamoorthy
- Division of Biotechnology, Manipal Life Sciences Centre, Manipal University, Manipal 576104, Karnataka State, India.
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Josephson R. Molecular cytogenetics: making it safe for human embryonic stem cells to enter the clinic. Expert Rev Mol Diagn 2014; 7:395-406. [PMID: 17620047 DOI: 10.1586/14737159.7.4.395] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Regenerative therapies based on transplantation of cells derived from human embryonic stem cells (hESC) are currently being prepared for clinical trials. Unfortunately, recent evidence indicates that many kinds of changes can occur to hESC during expansion in culture, and alterations to the growth control mechanisms may be required to establish hESC lines at all. Changes in the genome and epigenome can affect the validity of in vitro and animal studies, and put transplant recipients at increased risk of cancer. New molecular cytogenetic technologies enable us to examine the whole human genome with ever-finer resolution. This review describes several techniques for whole-genome analysis and the information they can provide about hESC lines. Adoption of high-resolution genotyping into routine characterization may prevent highly discouraging clinical outcomes.
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Lee JE, Hong EJ, Kim JH, Shin SY, Kim YY, Han BG. Instability at Short Tandem Repeats in Lymphoblastoid Cell Lines. Osong Public Health Res Perspect 2013; 4:194-6. [PMID: 24159555 PMCID: PMC3767104 DOI: 10.1016/j.phrp.2013.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 06/18/2013] [Accepted: 06/18/2013] [Indexed: 11/26/2022] Open
Abstract
Objectives Epstein Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) are a useful biological resource, however, genomic variations can happen during the generation and immortalization processes of LCLs. The purpose of this study was to identify genomic variations in LCL DNA compared with matched blood DNA using short tandem repeats (STRs) analysis. Methods We analyzed 15 STRs with blood DNA and their matched LCL DNA samples from 6645 unrelated healthy individuals. Results Mutations (such as repeat variations and triallelic patterns) of 15 STR loci were detected in 612 LCL DNAs (9.2% of total) without mutations in their matched blood DNA. The repeat variations of 15 STRs were detected in 526 LCL DNAs (mutation rate = 0.0792) and triallelic patterns were identified in 123 (mutation rate = 0.0185). Among 15 STRs, the most common repeat variations (n = 214, mutation rate = 0.0322) and triallelic patterns (n = 17, mutation rate = 0.0026) were found at FGA locus. Conclusion Our study shows that mutations in STRs can occur during generation and immortalization of LCLs.
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Affiliation(s)
- Jae-Eun Lee
- National Biobank of Korea, Korea National Institute of Health, Osong, Korea
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Yang R, Chen B, Pfütze K, Buch S, Steinke V, Holinski-Feder E, Stöcker S, von Schönfels W, Becker T, Schackert HK, Royer-Pokora B, Kloor M, Schmiegel WH, Büttner R, Engel C, Lascorz Puertolas J, Försti A, Kunkel N, Bugert P, Schreiber S, Krawczak M, Schafmayer C, Propping P, Hampe J, Hemminki K, Burwinkel B. Genome-wide analysis associates familial colorectal cancer with increases in copy number variations and a rare structural variation at 12p12.3. Carcinogenesis 2013; 35:315-23. [PMID: 24127187 DOI: 10.1093/carcin/bgt344] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the 'missing heritability' of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared with healthy controls, especially for CNVs larger than 50kb (case/control ratio = 1.66, P = 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2862 CRC cases but not in 6243 healthy controls (P = 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC-related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk and identify a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC.
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Affiliation(s)
- Rongxi Yang
- Molecular Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Schafer CM, Campbell NG, Cai G, Yu F, Makarov V, Yoon S, Daly MJ, Gibbs RA, Schellenberg GD, Devlin B, Sutcliffe JS, Buxbaum JD, Roeder K. Whole exome sequencing reveals minimal differences between cell line and whole blood derived DNA. Genomics 2013; 102:270-7. [PMID: 23743231 PMCID: PMC3812417 DOI: 10.1016/j.ygeno.2013.05.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Revised: 05/03/2013] [Accepted: 05/25/2013] [Indexed: 11/24/2022]
Abstract
Two common sources of DNA for whole exome sequencing (WES) are whole blood (WB) and immortalized lymphoblastoid cell line (LCL). However, it is possible that LCLs have a substantially higher rate of mutation than WB, causing concern for their use in sequencing studies. We compared results from paired WB and LCL DNA samples for 16 subjects, using LCLs of low passage number (<5). Using a standard analysis pipeline we detected a large number of discordant genotype calls (approximately 50 per subject) that we segregated into categories of "confidence" based on read-level quality metrics. From these categories and validation by Sanger sequencing, we estimate that the vast majority of the candidate differences were false positives and that our categories were effective in predicting valid sequence differences, including LCLs with putative mosaicism for the non-reference allele (3-4 per exome). These results validate the use of DNA from LCLs of low passage number for exome sequencing.
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Affiliation(s)
- Chad M. Schafer
- Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
| | - Nicholas G. Campbell
- Vanderbilt Brain Institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Guiqing Cai
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Fei Yu
- Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
| | - Vladimir Makarov
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Seungtai Yoon
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Mark J. Daly
- Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA
| | - Richard A. Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA
| | - Gerard D. Schellenberg
- Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Bernie Devlin
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA
| | - James S. Sutcliffe
- Vanderbilt Brain Institute, Departments of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University, Nashville, Tennessee 37232, USA
| | - Joseph D. Buxbaum
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Kathryn Roeder
- Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
- Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA
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48
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Hopman S, Merks J, Eussen H, Douben H, Snijder S, Hennekam R, de Klein A, Caron H. Structural genome variations in individuals with childhood cancer and tumour predisposition syndromes. Eur J Cancer 2013; 49:2170-8. [DOI: 10.1016/j.ejca.2013.02.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 01/02/2013] [Accepted: 02/03/2013] [Indexed: 11/15/2022]
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49
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Van Den Bossche MJ, Strazisar M, Cammaerts S, Liekens AM, Vandeweyer G, Depreeuw V, Mattheijssens M, Lenaerts AS, De Zutter S, De Rijk P, Sabbe B, Del-Favero J. Identification of rare copy number variants in high burden schizophrenia families. Am J Med Genet B Neuropsychiatr Genet 2013; 162B:273-82. [PMID: 23505263 DOI: 10.1002/ajmg.b.32146] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 02/13/2013] [Indexed: 11/05/2022]
Abstract
Over the last years, genome-wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the "common disease, rare variant" hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome-wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non-symptomatic causal CNV carriers in particular.
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Affiliation(s)
- Maarten J Van Den Bossche
- Applied Molecular Genomics Group, VIB Department of Molecular Genetics, VIB, Universiteitsplein 1, B-2610 Antwerp, Belgium
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50
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Comino-Méndez I, de Cubas AA, Bernal C, Álvarez-Escolá C, Sánchez-Malo C, Ramírez-Tortosa CL, Pedrinaci S, Rapizzi E, Ercolino T, Bernini G, Bacca A, Letón R, Pita G, Alonso MR, Leandro-García LJ, Gómez-Graña Á, Inglada-Pérez L, Mancikova V, Rodríguez-Antona C, Mannelli M, Robledo M, Cascón A. Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis. Hum Mol Genet 2013; 22:2169-76. [DOI: 10.1093/hmg/ddt069] [Citation(s) in RCA: 128] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
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