title: Transcriptional consequences of 16p11.2 deletion and duplication in mouse cortex and multiplex autism families.
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.
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Blumenthal
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Ragavendran
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Serkan
authors.initials: S
authors.lastname: Erdin
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Lambertus
authors.initials: L
authors.lastname: Klei
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Aarathi
authors.initials: A
authors.lastname: Sugathan
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Jolene R
authors.initials: JR
authors.lastname: Guide
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Poornima
authors.initials: P
authors.lastname: Manavalan
authors.affiliation: Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Julian Q
authors.initials: JQ
authors.lastname: Zhou
authors.affiliation: Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Levin
authors.affiliation: Department of Psychiatry, McGill University, Douglas Hospital Research Institute, Montreal, QC H4H 1R3, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Ernst
authors.affiliation: Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.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.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.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.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology; D002648:Child; D002872:Chromosome Deletion; D058674:Chromosome Duplication; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D051379:Mice; D010375:Pedigree; D010641:Phenotype; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic