DOCSLIB.ORG

Whole Exome Sequencing in Recurrent Early Pregnancy Loss

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Whole Exome Sequencing in Recurrent Early Pregnancy Loss Molecular Human Reproduction, Vol.22, No.5 pp. 364–372, 2016 Advanced Access publication on January 28, 2016 doi:10.1093/molehr/gaw008 ORIGINAL RESEARCH Whole exome sequencing in recurrent early pregnancy loss Ying Qiao1, Jiadi Wen2, Flamingo Tang1,SallyMartell1, Naomi Shomer1, Peter C.K. Leung3, Mary D. Stephenson4, and Evica Rajcan-Separovic1,* 1Department of Pathology, BC Child and Family Research Institute (CFRI), University of British Columbia (UBC), Vancouver, BC, Canada 2University of Texas, Dallas, TX, USA 3Department of Obstetrics and Gynaecology, University of British Columbia, Vancouver, BC, Canada V6Z 2 K5 4University of Chicago and University of Illinois at Chicago, Chicago, IL, USA *Correspondence address. Department of Pathology (Cytogenetics), BC Child and Family Research Institute, University of British Columbia, 950 West 28th, Room 3060, Vancouver, BC, Canada V5Z 4H4. Tel: +1-604-875-3121; Fax: +1-604-875-3601; E-mail: [email protected] Submitted on December 11, 2015; resubmitted on January 18, 2016; accepted on January 25, 2016 study hypothesis: Exome sequencing can identify genetic causes of idiopathic recurrent pregnancy loss (RPL). study finding: We identified compound heterozygous deleterious mutations affecting DYNC2H1 and ALOX15 in two out of four families with RPL. Both genes have a role in early development. Bioinformatics analysis of all genes with rare and putatively pathogenic mutations in mis- carriages and couples showed enrichment in pathways relevant to pregnancy loss, including the complement and coagulation cascades pathways. what is known already: Next generation sequencing (NGS) is increasingly being used to identify known and novel gene mutations in children with developmental delay and in fetuses with ultrasound-detected anomalies. In contrast, NGS is rarely used to study pregnancy loss. Chromosome microarray analysis detects putatively causative DNA copy number variants (CNVs) in 2% of miscarriages and CNVs of unknown significance (predominantly parental in origin) in up to 40% of miscarriages. Therefore, a large number of miscarriages still have an unknown cause. study design, samples/materials, methods: Whole exome sequencing (WES) was performed using Illumina HiSeq 2000 platformon seveneuploid miscarriages from four families with RPL. Golden Helix SVS v8.1.5 was used for data assessment and inheritance analysis for deleterious DNA variants predicted to severely disrupt protein-coding genes by introducing a frameshift, loss of the stop codon, gain of the stop codon, changes in splicing or the initial codon. Webgestalt (http://bioinfo.vanderbilt.edu/webgestalt/) was used for pathway and disease association enrichment analysis of a gene pool containing putatively pathogenic variants in miscarriages and couples in comparison to control gene pools. main results and the role of chance: Compound heterozygous mutations in DYNC2H1 and ALOX15 were identified in mis- carriages from two families with RPL. DYNC2H1 is involved in cilia biogenesis and has been associated with fetal lethality in humans. ALOX15 is expressed in placenta and its dysregulation has been associated with inflammation, placental, dysfunction, abnormal oxidative stress response and angiogenesis. The pool of putatively pathogenic single nucleotide variants (SNVs) and small insertions and deletions (indels) detected in the miscarriages showed enrichment in ‘complement and coagulation cascades pathway’, and ‘ciliary motility disorders’. We conclude that CNVs, individual SNVs and pool of deleterious gene mutations identified by exome sequencing could contribute to RPL. limitations, reasons for caution: The size of our sample cohort is small. The functional effect of candidate mutations should be evaluated to determine whether the mutations are causative. wider implications of the findings: This is the first study to assess whether SNVs may contribute to the pathogenesis of miscarriage. Furthermore, our findings suggest that collective effect of mutations in relevant biological pathways could be implicated in RPL. study funding and competing interest(s): The study was funded by Canadian Institutes of Health Research (grant MOP 106467) and Michael Smith Foundation of Health Research Career Scholar salary award to ERS. Key words: recurrent pregnancy loss / whole exome sequencing / euploid miscarriages / compound heterozygous mutation / copy number variants / SNVs & The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected] Genetic causes of recurrent pregnancy loss 365 Introduction Filges et al., 2015). In all of these studies, the abnormal pregnancies inher- ited different mutations in a same gene from each parent, rendering the Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses, gene defective in the conceptus (compound heterozygous mutations). occursin 5%ofcouplestryingtoconceive(Sierra and Stephenson, 2006). The affected genes havebeenfound to participatein avarietyofbiological Both parental and embryo/fetal factors are associated with RPL. Parental processes important for embryonic/fetal development and fertility, such factors include parental translocations, maternal thyroid or prolactin as ciliogenesis (kinesin family member 14, KIF14 (Filges et al., 2014) and disease or diabetes mellitus, endometrial changes, intrauterine abnormal- intraflagellar transport 122, IFT122 (Tsurusaki et al., 2014)), RNA trans- ities and antiphospholipid antibodies (Stephenson and Kutteh, 2007). port and processing (nucleoporin, GLE1 (Ellard et al., 2015)), signal trans- Numericchromosomeerrorsintheconceptusarethemostcommon duction (ryanodine receptor 1, RYR1 (Ellard et al., 2015) and cholinergic cause of miscarriage, particularly in miscarriages occurring before 10 receptor, nicotinic alpha 1, CHRNA1 (Shamseldin et al., 2013)) and weeks of gestation (early miscarriages) (Kolte et al., 2015). Association of maternal meiosis II (phospholipase C delta 4, PLCD4 and oxysterol single-gene or multi-genic changes with miscarriage has been proposed binding protein-like 5, OSBPL5)(Filges et al., 2015). (Larsen et al., 2013), however, for the vast majority of the 40–50% of In this study, we have used exome sequencing to look for pathogenic miscarriages with a normal karyotype (euploid miscarriage), the genetic variants (single nucleotide variants, SNVs, and small insertions and etiology remains uncertain (Sierra and Stephenson, 2006). deletions, indels) in euploid early miscarriages from couples with RPL, The recent advent of genome-wide high-resolution technologies, who previously had high-resolution CMA analysis. Our expectation including chromosome microarray analysis (CMA) and next generation was that we will identify rare and deleterious SNVs or indels affecting sequencing (NGS), have opened new possibilities for discovery of both the maternal and paternal allele which would make the gene dys- genetic changes that are too small to be detected by traditional miscar- functional when both parental alleles are simultaneously transmitted to riage chromosome analysis. To date, reportedly over 3000 miscarriages the conceptus resulting in miscarriage. Recurrent inheritance of the have been studied using CMA technology, including those studied by our mutated alleles from both parents in miscarriages would support their group (Rajcan-Separovic et al., 2010a, b) and others (for review, see significance in abnormal development. In addition to analyzing single Bagheri et al., 2015). Clinically relevant copy number variants (CNVs) genes for mutations which could cause miscarriage, we further assessed were identified in 1.6% of cases (Levy et al., 2014), while rare variants the mutation ‘burden’ (i.e. sum of putatively pathogenic mutations in all of uncertain clinical significance (VUS) were seen in 1–40% of cases. genes) in the couples and miscarriages. Homozygosity affecting chromosomal segments, whole chromosomes and genomes occurred in 1–30% of cases (Robberecht et al., 2012; Bug et al., 2014; Levy et al., 2014). Although the impact of CNVs on Materials and Methods the function of affected genes in miscarriage was demonstrated for iso- lated CNVs (Wen et al., 2015), and CNVs as a group (Nagirnaja et al., Subjects 2014; Bagheri et al., 2015), the role of the majority of predominantly Couples with RPL and their miscarriages previously assessed by CMA (Rajcan- inherited miscarriage VUS remains uncertain (Rajcan-Separovic et al., Separovicetal., 2010a)wereselectedforexomesequencingbasedonavailabil- 2010a, b; Robberecht et al., 2012; Viaggi et al., 2013; Bug et al., 2014; ityofsufficientDNAfrom atleasttwo miscarriagesand thecoupleand absence Levy et al., 2014; Bagheri et al., 2015), leaving the cause of euploid of clearly pathogenic CNVs at the time of exome analysis. Seven miscarriages miscarriages unresolved. were subjectedfor WES: two miscarriageseach from threefamilies(Family 4,6 and 9) and one miscarriage from Family 12. The presence of candidate variants More recently, the development and application of NGS, including determined in exome sequenced miscarriage from Family 12 was then tested whole genome or whole exome sequencing (WES), allowed screening by Sanger sequencing in the second miscarriage and the couple. Both partners the whole genome for new genetic causes of human disease at the nu- from three families (4, 6 and 9) had their exomes sequenced. cleotide level (Koboldt et al., 2013). Thus far,
Load more

Recommended publications
  • Transcriptional Regulation of RKIP in Prostate Cancer Progression
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Sciences Transcriptional Regulation of RKIP in Prostate Cancer Progression Submitted by: Sandra Marie Beach In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences Examination Committee Major Advisor: Kam Yeung, Ph.D. Academic William Maltese, Ph.D. Advisory Committee: Sonia Najjar, Ph.D. Han-Fei Ding, M.D., Ph.D. Manohar Ratnam, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: May 16, 2007 Transcriptional Regulation of RKIP in Prostate Cancer Progression Sandra Beach University of Toledo ACKNOWLDEGMENTS I thank my major advisor, Dr. Kam Yeung, for the opportunity to pursue my degree in his laboratory. I am also indebted to my advisory committee members past and present, Drs. Sonia Najjar, Han-Fei Ding, Manohar Ratnam, James Trempe, and Douglas Pittman for generously and judiciously guiding my studies and sharing reagents and equipment. I owe extended thanks to Dr. William Maltese as a committee member and chairman of my department for supporting my degree progress. The entire Department of Biochemistry and Cancer Biology has been most kind and helpful to me. Drs. Roy Collaco and Hong-Juan Cui have shared their excellent technical and practical advice with me throughout my studies. I thank members of the Yeung laboratory, Dr. Sungdae Park, Hui Hui Tang, Miranda Yeung for their support and collegiality. The data mining studies herein would not have been possible without the helpful advice of Dr. Robert Trumbly. I am also grateful for the exceptional assistance and shared microarray data of Dr.
    [Show full text]
  • Microduplication of Xp22.31 and MECP2 Pathogenic Variant in a Girl with Rett Syndrome: a Case Report
    IJMS Vol 44, No 4, July 2019 Case Report Microduplication of Xp22.31 and MECP2 Pathogenic Variant in a Girl with Rett Syndrome: A Case Report Estephania Candelo1, MD, MSc; Abstract Diana Ramirez-Montaño1, MD, MSc; Harry Pachajoa1,2, MD, PhD Rett syndrome (RS) is a neurodevelopmental infantile disease characterized by an early normal psychomotor development followed by a regression in the acquisition of normal developmental stages. In the majority of cases, it leads to a sporadic mutation in the 1Center for Research on Congenital MECP2 gene, which is located on the X chromosome. However, Anomalies and Rare Diseases (CIACER), Health Sciences Faculty, this syndrome has also been associated with microdeletions, gene L Building, Universidad Icesi, Cali, translocations, and other gene mutations. A 12-year-old female Colombia; Colombian patient was presented with refractory epilepsy and 2Department of Genetics, Fundación Valle del Lili, Cali, Colombia regression in skill acquisition (especially language with motor and verbal stereotypies, hyperactivity, and autistic spectrum Correspondence: Harry Pachajoa, MD, PhD; disorder criteria). The patient was born to non-consanguineous Center for Research on Congenital parents and had an early normal development until the age of 36 Anomalies and Rare Diseases months. Comparative genomic hybridization array-CGH (750K) (CIACER), Health Sciences Faculty, L Building, ZIP: 760031, Universidad Icesi, was performed and Xp22.31 duplication was detected (6866889- Cali, Colombia 8115153) with a size of 1.248 Mb associated with developmental Tel: +57 2 5552334, Ext: 8075 delay, epilepsy, and autistic traits. Given the clinical criteria of Fax: +57 2 5551441 Email: [email protected] RS, MECP2 sequencing was performed which showed a de novo Received: 03 June 2018 pathogenic variant c.338C>G (p.Pro113Arg).
    [Show full text]
  • Downloaded from [266]
    Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation by Allison Marie Cotton B.Sc., The University of Guelph, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate Studies (Medical Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) January 2012 © Allison Marie Cotton, 2012 Abstract The process of X-chromosome inactivation achieves dosage compensation between mammalian males and females. In females one X chromosome is transcriptionally silenced through a variety of epigenetic modifications including DNA methylation. Most X-linked genes are subject to X-chromosome inactivation and only expressed from the active X chromosome. On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome inactivation are methylated in their promoter regions, while genes which escape from X- chromosome inactivation have unmethylated CpG island promoters on both the active and inactive X chromosomes. The first objective of this thesis was to determine if the DNA methylation of CpG island promoters could be used to accurately predict X chromosome inactivation status. The second objective was to use DNA methylation to predict X-chromosome inactivation status in a variety of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four times higher escape from X-chromosome inactivation than in any other tissue. Despite the hypomethylation of repetitive elements on both the X chromosome and the autosomes, no changes were detected in the frequency or intensity of placental Cot-1 holes.
    [Show full text]
  • Extensive Genomic and Transcriptional Diversity Identified Through Massively Parallel DNA and RNA Sequencing of Eighteen Korean Individuals
    ARTICLES Extensive genomic and transcriptional diversity identified through massively parallel DNA and RNA sequencing of eighteen Korean individuals Young Seok Ju1,2,9, Jong-Il Kim1,3–5,9, Sheehyun Kim1,2,9, Dongwan Hong1,8, Hansoo Park1,6, Jong-Yeon Shin1,5, Seungbok Lee1,4, Won-Chul Lee1,4, Sujung Kim5, Saet-Byeol Yu5, Sung-Soo Park5, Seung-Hyun Seo5, Ji-Young Yun5, Hyun-Jin Kim1,4, Dong-Sung Lee1,4, Maryam Yavartanoo1,4, Hyunseok Peter Kang1, Omer Gokcumen6, Diddahally R Govindaraju6, Jung Hee Jung2, Hyonyong Chong2,7, Kap-Seok Yang2, Hyungtae Kim2, Charles Lee6 & Jeong-Sun Seo1–5,7 Massively parallel sequencing technologies have identified a broad spectrum of human genome diversity. Here we deep sequenced and correlated 18 genomes and 17 transcriptomes of unrelated Korean individuals. This has allowed us to construct a genome- wide map of common and rare variants and also identify variants formed during DNA-RNA transcription. We identified 9.56 million genomic variants, 23.2% of which appear to be previously unidentified. From transcriptome sequencing, we discovered 4,414 transcripts not previously annotated. Finally, we revealed 1,809 sites of transcriptional base modification, where the transcriptional landscape is different from the corresponding genomic sequences, and 580 sites of allele-specific expression. Our findings suggest that a considerable number of unexplored genomic variants still remain to be identified in the human genome, and that the integrated analysis of genome and transcriptome sequencing is powerful for understanding the diversity and functional aspects of human genomic variants. Massively parallel sequencing technologies have revolutionized traits has actually been explained18, presumably because, in part, of our understanding of human genome architecture.
    [Show full text]
  • Meta-Analyses of Expression Profiling Data in the Postmortem
    META-ANALYSES OF EXPRESSION PROFILING DATA IN THE POSTMORTEM HUMAN BRAIN by Meeta Mistry B.Sc., McMaster University, 2005 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Bioinformatics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2012 © Meeta Mistry, 2012 Abstract Schizophrenia is a severe psychiatric illness for which the precise etiology remains unknown. Studies using postmortem human brain have become increasingly important in schizophrenia research, providing an opportunity to directly investigate the diseased brain tissue. Gene expression profiling technologies have been used by a number of groups to explore the postmortem human brain and seek genes which show changes in expression correlated with schizophrenia. While this has been a valuable means of generating hypotheses, there is a general lack of consensus in the findings across studies. Expression profiling of postmortem human brain tissue is difficult due to the effect of various factors that can confound the data. The first aim of this thesis was to use control postmortem human cortex for identification of expression changes associated with several factors, specifically: age, sex, brain pH and postmortem interval. I conducted a meta-analysis across the control arm of eleven microarray datasets (representing over 400 subjects), and identified a signature of genes associated with each factor. These genes provide critical information towards the identification of problematic genes when investigating postmortem human brain in schizophrenia and other neuropsychiatric illnesses. The second aim of this thesis was to evaluate gene expression patterns in the prefrontal cortex associated with schizophrenia by exploring two methods of analysis: differential expression and coexpression.
    [Show full text]
  • OTX2 Homeoprotein Functions in Adult Choroid Plexus
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.28.441734; this version posted April 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. OTX2 homeoprotein functions in adult choroid plexus Anabelle Planques1†, Vanessa Oliveira Moreira1†, David Benacom1, Clémence Bernard1, Laurent Jourdren2, Corinne Blugeon2, Florent Dingli3, Vanessa Masson3, Damarys Loew3, Alain Prochiantz1,4, Ariel A. Di Nardo1* 1. Centre for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS UMR7241, INSERM U1050, Labex MemoLife, PSL University, Paris, France 2. Genomics Core Facility, Institut de Biologie de l’ENS (IBENS), Département de Biologie, École Normale Supérieure, CNRS, INSERM, PSL University, 75005 Paris, France 3. Institut Curie, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, 75248 Paris Cedex 05, France 4. Institute of Neurosciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China †contributed equally *corresponding author: [email protected] Abstract Choroid plexus secretes cerebrospinal fluid important for brain development and homeostasis. The OTX2 homeoprotein is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative roles for OTX2 in choroid plexus function, including cell signaling and adhesion, and show that it regulates the expression of factors secreted into cerebrospinal fluid, notably transthyretin. We show that Otx2 expression impacts choroid plexus immune and stress responses, and also affects splicing which leads to changes in mRNA isoforms of proteins implicated in oxidative stress response and DNA repair.
    [Show full text]
  • Identification of Novel Genes for X-Linked Mental Retardation
    20.\o. ldent¡f¡cat¡on of Novel Genes for X-linked Mental Retardation Adelaide A thesis submitted for the degree of Dootor of Philosophy to the University of by Marie Mangelsdorf BSc (Hons) School ofMedicine Department of Paediatrics, Women's and Children's Hospital May 2003 Corrections The following references should be referred to in the text as: Page 2,line 2: (Birch et al., 1970) Page 2,line 2: (Moser et al., 1983) Page 3, line 15: (Martin and Bell, 1943) Page 3, line 4 and line 9: (Stevenson et a1.,2000) Page 77,line 5: (Monaco et a|.,1986) And in the reference list as: Birch H. G., Richardson S. ,{., Baird D., Horobin, G. and Ilsley, R. (1970) Mental Subnormality in the Community: A Clinical and Epidemiological Study. Williams and Wilkins, Baltimore. Martin J. P. and Bell J. (1943). A pedigree of mental defect showing sex-linkage . J. Neurol. Psychiatry 6: 154. Monaco 4.P., Nerve R.L., Colletti-Feener C., Bertelson C.J., Kurnit D.M. and Kunkel L.M. (1986) Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 3232 646-650. Moser H.W., Ramey C.T. and Leonard C.O. (1933) In Principles and Practice of Medical Genetics (Emery A.E.H. and Rimoin D.L., Eds). Churchill Livingstone, Edinburgh UK Penrose L. (1938) A clinical and genetic study of 1280 cases of mental defect. (The Colchester survey). Medical Research Council, London, UK. Stevenson R.E., Schwartz C.E. and Schroer R.J. (2000) X-linked Mental Retardation. Oxford University Press.
    [Show full text]
  • Biological Models of Colorectal Cancer Metastasis and Tumor Suppression
    BIOLOGICAL MODELS OF COLORECTAL CANCER METASTASIS AND TUMOR SUPPRESSION PROVIDE MECHANISTIC INSIGHTS TO GUIDE PERSONALIZED CARE OF THE COLORECTAL CANCER PATIENT By Jesse Joshua Smith Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University In partial fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY In Cell and Developmental Biology May, 2010 Nashville, Tennessee Approved: Professor R. Daniel Beauchamp Professor Robert J. Coffey Professor Mark deCaestecker Professor Ethan Lee Professor Steven K. Hanks Copyright 2010 by Jesse Joshua Smith All Rights Reserved To my grandparents, Gladys and A.L. Lyth and Juanda Ruth and J.E. Smith, fully supportive and never in doubt. To my amazing and enduring parents, Rebecca Lyth and Jesse E. Smith, Jr., always there for me. .my sure foundation. To Jeannine, Bill and Reagan for encouragement, patience, love, trust and a solid backing. To Granny George and Shawn for loving support and care. And To my beautiful wife, Kelly, My heart, soul and great love, Infinitely supportive, patient and graceful. ii ACKNOWLEDGEMENTS This work would not have been possible without the financial support of the Vanderbilt Medical Scientist Training Program through the Clinical and Translational Science Award (Clinical Investigator Track), the Society of University Surgeons-Ethicon Scholarship Fund and the Surgical Oncology T32 grant and the Vanderbilt Medical Center Section of Surgical Sciences and the Department of Surgical Oncology. I am especially indebted to Drs. R. Daniel Beauchamp, Chairman of the Section of Surgical Sciences, Dr. James R. Goldenring, Vice Chairman of Research of the Department of Surgery, Dr. Naji N.
    [Show full text]
  • A Transcriptional Signature of Postmitotic Maintenance in Neural Tissues
    Neurobiology of Aging 74 (2019) 147e160 Contents lists available at ScienceDirect Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging Postmitotic cell longevityeassociated genes: a transcriptional signature of postmitotic maintenance in neural tissues Atahualpa Castillo-Morales a,b, Jimena Monzón-Sandoval a,b, Araxi O. Urrutia b,c,*, Humberto Gutiérrez a,** a School of Life Sciences, University of Lincoln, Lincoln, UK b Milner Centre for Evolution, Department of Biology and Biochemistry, University of Bath, Bath, UK c Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, Mexico article info abstract Article history: Different cell types have different postmitotic maintenance requirements. Nerve cells, however, are Received 11 April 2018 unique in this respect as they need to survive and preserve their functional complexity for the entire Received in revised form 3 October 2018 lifetime of the organism, and failure at any level of their supporting mechanisms leads to a wide range of Accepted 11 October 2018 neurodegenerative conditions. Whether these differences across tissues arise from the activation of Available online 19 October 2018 distinct cell typeespecific maintenance mechanisms or the differential activation of a common molecular repertoire is not known. To identify the transcriptional signature of postmitotic cellular longevity (PMCL), Keywords: we compared whole-genome transcriptome data from human tissues ranging in longevity from 120 days Neural maintenance Cell longevity to over 70 years and found a set of 81 genes whose expression levels are closely associated with Transcriptional signature increased cell longevity. Using expression data from 10 independent sources, we found that these genes Functional genomics are more highly coexpressed in longer-living tissues and are enriched in specific biological processes and transcription factor targets compared with randomly selected gene samples.
    [Show full text]
  • Abstracts from the 51St European Society of Human Genetics Conference: Electronic Posters
    European Journal of Human Genetics (2019) 27:870–1041 https://doi.org/10.1038/s41431-019-0408-3 MEETING ABSTRACTS Abstracts from the 51st European Society of Human Genetics Conference: Electronic Posters © European Society of Human Genetics 2019 June 16–19, 2018, Fiera Milano Congressi, Milan Italy Sponsorship: Publication of this supplement was sponsored by the European Society of Human Genetics. All content was reviewed and approved by the ESHG Scientific Programme Committee, which held full responsibility for the abstract selections. Disclosure Information: In order to help readers form their own judgments of potential bias in published abstracts, authors are asked to declare any competing financial interests. Contributions of up to EUR 10 000.- (Ten thousand Euros, or equivalent value in kind) per year per company are considered "Modest". Contributions above EUR 10 000.- per year are considered "Significant". 1234567890();,: 1234567890();,: E-P01 Reproductive Genetics/Prenatal Genetics then compared this data to de novo cases where research based PO studies were completed (N=57) in NY. E-P01.01 Results: MFSIQ (66.4) for familial deletions was Parent of origin in familial 22q11.2 deletions impacts full statistically lower (p = .01) than for de novo deletions scale intelligence quotient scores (N=399, MFSIQ=76.2). MFSIQ for children with mater- nally inherited deletions (63.7) was statistically lower D. E. McGinn1,2, M. Unolt3,4, T. B. Crowley1, B. S. Emanuel1,5, (p = .03) than for paternally inherited deletions (72.0). As E. H. Zackai1,5, E. Moss1, B. Morrow6, B. Nowakowska7,J. compared with the NY cohort where the MFSIQ for Vermeesch8, A.
    [Show full text]
  • Specific Gene Expression Differences in Response to Injury
    Human and Murine Kidneys Show Gender- and Species- Specific Gene Expression Differences in Response to Injury Han Si1, Ramandeep S. Banga1, Pinelopi Kapitsinou1, Manjunath Ramaiah1, Janis Lawrence1, Ganesh Kambhampati1, Antje Gruenwald1, Erwin Bottinger4, Daniel Glicklich1, Vivian Tellis2, Stuart Greenstein2, David B. Thomas3, James Pullman3, Melissa Fazzari5, Katalin Susztak1* 1 Department of Medicine/Nephrology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 2 Department of Surgery, Montefiore Medical Center, Bronx, New York, United States of America, 3 Department of Pathology, Montefiore Medical Center, Bronx, New York, United States of America, 4 Department of Medicine/Nephrology, Mount Sinai School of Medicine, New York, United States of America, 5 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America Abstract The incidence of End Stage Renal Disease (ESRD) is approximately 50% higher in men than women. In order to understand the molecular basis of this gender disparity, we examined sex specific gene expression patterns in control and diseased, human and murine kidney samples. Using the Affymetrix platform we performed comprehensive gene expression analysis on 42 microdissected human kidney samples (glomeruli and tubules). We identified 67 genes with gender biased expression in healthy human kidneys and 24 transcripts in diseased male and female human kidneys. Similar analysis performed in mice using male and female control and doxorubicin induced nephrotic syndrome kidneys identified significantly larger number of differentially expressed transcripts. The majority of genes showing gender biased expression either in diseased human and murine kidneys were different from those differentially expressed in healthy kidneys.
    [Show full text]
  • Copy Number Gain of VCX, X-Linked Multi-Copy Gene, Leads to Cell Proliferation and Apoptosis During Spermatogenesis
    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 48 Research Paper Copy number gain of VCX, X-linked multi-copy gene, leads to cell proliferation and apoptosis during spermatogenesis Juan Ji1,2,4,*, Yufeng Qin3,*, Rong Wang5,*, Zhenyao Huang1,2, Yan Zhang1,2, Ran Zhou1,2, Ling Song1,2, Xiufeng Ling4, Zhibin Hu1,6, Dengshun Miao1,5, Hongbing Shen1,6, Yankai Xia1,2, Xinru Wang1,2, Chuncheng Lu1,2 1State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, China 2Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China 3Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA 4Department of Children Health Care, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing, China 5Research Center for Bone and Stem Cells, Department of Anatomy, Histology, and Embryology, Nanjing Medical University, Nanjing, China 6Department of Epidemiology and Biostatistics and Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China *These authors contributed equally to this work and joint first authors Correspondence to: Chuncheng Lu, email: [email protected] Keywords: copy number variations, non-obstructive azoospermia Received: April 08, 2016 Accepted: September 25, 2016 Published: October 01, 2016 ABSTRACT Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. In recent years there has been increasing evidence to implicate the participation of X chromosome in the process of spermatogenesis.
    [Show full text]