Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families.
Identifieur interne : 000B14 ( Main/Exploration ); précédent : 000B13; suivant : 000B15Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families.
Auteurs : Ian Blumenthal [États-Unis] ; Ashok Ragavendran [États-Unis] ; Serkan Erdin [États-Unis] ; Lambertus Klei [États-Unis] ; Aarathi Sugathan [États-Unis] ; Jolene R. Guide [États-Unis] ; Poornima Manavalan [États-Unis] ; Julian Q. Zhou [États-Unis] ; Vanessa C. Wheeler [États-Unis] ; Joshua Z. Levin [États-Unis] ; Carl Ernst [Canada] ; Kathryn Roeder [États-Unis] ; Bernie Devlin [États-Unis] ; James F. Gusella [États-Unis] ; Michael E. Talkowski [États-Unis]Source :
- American journal of human genetics [ 1537-6605 ] ; 2014.
Descripteurs français
- KwdFr :
- Analyse de séquence d'ARN, Animaux, Chromosomes humains de la paire 16 (génétique), Cortex cérébral (anatomopathologie), Duplication chromosomique, Déficience intellectuelle (génétique), Délétion de segment de chromosome, Enfant, Femelle, Génotype, Humains, Mâle, Pedigree, Phénotype, Souris, Transcription génétique, Trouble autistique (génétique), Variations de nombre de copies de segment d'ADN, Étude d'association pangénomique.
- MESH :
- anatomopathologie : Cortex cérébral.
- génétique : Chromosomes humains de la paire 16, Déficience intellectuelle, Trouble autistique.
- Analyse de séquence d'ARN, Animaux, Duplication chromosomique, Délétion de segment de chromosome, Enfant, Femelle, Génotype, Humains, Mâle, Pedigree, Phénotype, Souris, Transcription génétique, Variations de nombre de copies de segment d'ADN, Étude d'association pangénomique.
English descriptors
- KwdEn :
- Animals, Autistic Disorder (genetics), Cerebral Cortex (pathology), Child, Chromosome Deletion, Chromosome Duplication, Chromosomes, Human, Pair 16 (genetics), DNA Copy Number Variations, Female, Genome-Wide Association Study, Genotype, Humans, Intellectual Disability (genetics), Male, Mice, Pedigree, Phenotype, Sequence Analysis, RNA, Transcription, Genetic.
- MESH :
- genetics : Autistic Disorder, Chromosomes, Human, Pair 16, Intellectual Disability.
- pathology : Cerebral Cortex.
- Animals, Child, Chromosome Deletion, Chromosome Duplication, DNA Copy Number Variations, Female, Genome-Wide Association Study, Genotype, Humans, Male, Mice, Pedigree, Phenotype, Sequence Analysis, RNA, Transcription, Genetic.
Abstract
Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis.
DOI: 10.1016/j.ajhg.2014.05.004
PubMed: 24906019
Affiliations:
- Canada, États-Unis
- Massachusetts, Pennsylvanie, Québec
- Montréal, Pittsburgh
- Université Carnegie-Mellon, Université McGill
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Le document en format XML
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wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Ragavendran, Ashok" sort="Ragavendran, Ashok" uniqKey="Ragavendran A" first="Ashok" last="Ragavendran">Ashok Ragavendran</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Erdin, Serkan" sort="Erdin, Serkan" uniqKey="Erdin S" first="Serkan" last="Erdin">Serkan Erdin</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name><affiliation wicri:level="2"><nlm:affiliation>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Sugathan, Aarathi" sort="Sugathan, Aarathi" uniqKey="Sugathan A" first="Aarathi" last="Sugathan">Aarathi Sugathan</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Guide, Jolene R" sort="Guide, Jolene R" uniqKey="Guide J" first="Jolene R" last="Guide">Jolene R. Guide</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Manavalan, Poornima" sort="Manavalan, Poornima" uniqKey="Manavalan P" first="Poornima" last="Manavalan">Poornima Manavalan</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Zhou, Julian Q" sort="Zhou, Julian Q" uniqKey="Zhou J" first="Julian Q" last="Zhou">Julian Q. Zhou</name><affiliation wicri:level="4"><nlm:affiliation>Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université Carnegie-Mellon</orgName></affiliation></author><author><name sortKey="Wheeler, Vanessa C" sort="Wheeler, Vanessa C" uniqKey="Wheeler V" first="Vanessa C" last="Wheeler">Vanessa C. Wheeler</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Levin, Joshua Z" sort="Levin, Joshua Z" uniqKey="Levin J" first="Joshua Z" last="Levin">Joshua Z. Levin</name><affiliation wicri:level="2"><nlm:affiliation>Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Ernst, Carl" sort="Ernst, Carl" uniqKey="Ernst C" first="Carl" last="Ernst">Carl Ernst</name><affiliation wicri:level="4"><nlm:affiliation>Department of Psychiatry, McGill University, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Psychiatry, McGill University, Douglas Hospital Research Institute, Montreal, QC H4H 1R3</wicri:regionArea><orgName type="university">Université McGill</orgName><placeName><settlement type="city">Montréal</settlement><region type="state">Québec</region></placeName></affiliation></author><author><name sortKey="Roeder, Kathryn" sort="Roeder, Kathryn" uniqKey="Roeder K" first="Kathryn" last="Roeder">Kathryn Roeder</name><affiliation wicri:level="4"><nlm:affiliation>Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université Carnegie-Mellon</orgName></affiliation></author><author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name><affiliation wicri:level="2"><nlm:affiliation>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author><author><name sortKey="Gusella, James F" sort="Gusella, James F" uniqKey="Gusella J" first="James F" last="Gusella">James F. Gusella</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Departments of Neurology, Genetics, Psychiatry, and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02141, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Departments of Neurology, Genetics, Psychiatry, and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02141</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Talkowski, Michael E" sort="Talkowski, Michael E" uniqKey="Talkowski M" first="Michael E" last="Talkowski">Michael E. Talkowski</name><affiliation wicri:level="2"><nlm:affiliation>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Departments of Neurology, Genetics, Psychiatry, and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02141, USA. Electronic address: talkowski@chgr.mgh.harvard.edu.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA; Departments of Neurology, Genetics, Psychiatry, and Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02141</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author></analytic><series><title level="j">American journal of human genetics</title><idno type="eISSN">1537-6605</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Autistic Disorder (genetics)</term><term>Cerebral Cortex (pathology)</term><term>Child</term><term>Chromosome Deletion</term><term>Chromosome Duplication</term><term>Chromosomes, Human, Pair 16 (genetics)</term><term>DNA Copy Number Variations</term><term>Female</term><term>Genome-Wide Association Study</term><term>Genotype</term><term>Humans</term><term>Intellectual Disability (genetics)</term><term>Male</term><term>Mice</term><term>Pedigree</term><term>Phenotype</term><term>Sequence Analysis, RNA</term><term>Transcription, Genetic</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de séquence d'ARN</term><term>Animaux</term><term>Chromosomes humains de la paire 16 (génétique)</term><term>Cortex cérébral (anatomopathologie)</term><term>Duplication chromosomique</term><term>Déficience intellectuelle (génétique)</term><term>Délétion de segment de chromosome</term><term>Enfant</term><term>Femelle</term><term>Génotype</term><term>Humains</term><term>Mâle</term><term>Pedigree</term><term>Phénotype</term><term>Souris</term><term>Transcription génétique</term><term>Trouble autistique (génétique)</term><term>Variations de nombre de copies de segment d'ADN</term><term>Étude d'association pangénomique</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Cortex cérébral</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Autistic Disorder</term><term>Chromosomes, Human, Pair 16</term><term>Intellectual Disability</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Chromosomes humains de la paire 16</term><term>Déficience intellectuelle</term><term>Trouble autistique</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Cerebral Cortex</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Child</term><term>Chromosome Deletion</term><term>Chromosome Duplication</term><term>DNA Copy Number Variations</term><term>Female</term><term>Genome-Wide Association Study</term><term>Genotype</term><term>Humans</term><term>Male</term><term>Mice</term><term>Pedigree</term><term>Phenotype</term><term>Sequence Analysis, RNA</term><term>Transcription, Genetic</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de séquence d'ARN</term><term>Animaux</term><term>Duplication chromosomique</term><term>Délétion de segment de chromosome</term><term>Enfant</term><term>Femelle</term><term>Génotype</term><term>Humains</term><term>Mâle</term><term>Pedigree</term><term>Phénotype</term><term>Souris</term><term>Transcription génétique</term><term>Variations de nombre de copies de segment d'ADN</term><term>Étude d'association pangénomique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Massachusetts</li><li>Pennsylvanie</li><li>Québec</li></region><settlement><li>Montréal</li><li>Pittsburgh</li></settlement><orgName><li>Université Carnegie-Mellon</li><li>Université McGill</li></orgName></list><tree><country name="États-Unis"><region name="Massachusetts"><name sortKey="Blumenthal, Ian" sort="Blumenthal, Ian" uniqKey="Blumenthal I" first="Ian" last="Blumenthal">Ian Blumenthal</name></region><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name><name sortKey="Erdin, Serkan" sort="Erdin, Serkan" uniqKey="Erdin S" first="Serkan" last="Erdin">Serkan Erdin</name><name sortKey="Guide, Jolene R" sort="Guide, Jolene R" uniqKey="Guide J" first="Jolene R" last="Guide">Jolene R. Guide</name><name sortKey="Gusella, James F" sort="Gusella, James F" uniqKey="Gusella J" first="James F" last="Gusella">James F. Gusella</name><name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name><name sortKey="Levin, Joshua Z" sort="Levin, Joshua Z" uniqKey="Levin J" first="Joshua Z" last="Levin">Joshua Z. Levin</name><name sortKey="Manavalan, Poornima" sort="Manavalan, Poornima" uniqKey="Manavalan P" first="Poornima" last="Manavalan">Poornima Manavalan</name><name sortKey="Ragavendran, Ashok" sort="Ragavendran, Ashok" uniqKey="Ragavendran A" first="Ashok" last="Ragavendran">Ashok Ragavendran</name><name sortKey="Roeder, Kathryn" sort="Roeder, Kathryn" uniqKey="Roeder K" first="Kathryn" last="Roeder">Kathryn Roeder</name><name sortKey="Sugathan, Aarathi" sort="Sugathan, Aarathi" uniqKey="Sugathan A" first="Aarathi" last="Sugathan">Aarathi Sugathan</name><name sortKey="Talkowski, Michael E" sort="Talkowski, Michael E" uniqKey="Talkowski M" first="Michael E" last="Talkowski">Michael E. Talkowski</name><name sortKey="Wheeler, Vanessa C" sort="Wheeler, Vanessa C" uniqKey="Wheeler V" first="Vanessa C" last="Wheeler">Vanessa C. Wheeler</name><name sortKey="Zhou, Julian Q" sort="Zhou, Julian Q" uniqKey="Zhou J" first="Julian Q" last="Zhou">Julian Q. Zhou</name></country><country name="Canada"><region name="Québec"><name sortKey="Ernst, Carl" sort="Ernst, Carl" uniqKey="Ernst C" first="Carl" last="Ernst">Carl Ernst</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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