Mouse Shank1 Conditional Knockout Project (CRISPR/Cas9)
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Deciphering the Molecular Profile of Plaques, Memory Decline And
ORIGINAL RESEARCH ARTICLE published: 16 April 2014 AGING NEUROSCIENCE doi: 10.3389/fnagi.2014.00075 Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer’s disease by deep sequencing Yvonne Bouter 1†,Tim Kacprowski 2,3†, Robert Weissmann4, Katharina Dietrich1, Henning Borgers 1, Andreas Brauß1, Christian Sperling 4, Oliver Wirths 1, Mario Albrecht 2,5, Lars R. Jensen4, Andreas W. Kuss 4* andThomas A. Bayer 1* 1 Division of Molecular Psychiatry, Georg-August-University Goettingen, University Medicine Goettingen, Goettingen, Germany 2 Department of Bioinformatics, Institute of Biometrics and Medical Informatics, University Medicine Greifswald, Greifswald, Germany 3 Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany 4 Human Molecular Genetics, Department for Human Genetics of the Institute for Genetics and Functional Genomics, Institute for Human Genetics, University Medicine Greifswald, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany 5 Institute for Knowledge Discovery, Graz University of Technology, Graz, Austria Edited by: One of the central research questions on the etiology of Alzheimer’s disease (AD) is the Isidro Ferrer, University of Barcelona, elucidation of the molecular signatures triggered by the amyloid cascade of pathological Spain events. Next-generation sequencing allows the identification of genes involved in disease Reviewed by: Isidro Ferrer, University of Barcelona, processes in an unbiased manner. We have combined this technique with the analysis of Spain two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneu- Dietmar R. Thal, University of Ulm, ronal Ab aggregation, neuron loss, and behavioral deficits. (2)TheTg4–42 model expresses Germany N-truncated Ab4–42 and develops neuron loss and behavioral deficits albeit without plaque *Correspondence: formation. -
Supplementary Table 1. Mutated Genes That Contain Protein Domains Identified Through Mutation Enrichment Analysis
Supplementary Table 1. Mutated genes that contain protein domains identified through mutation enrichment analysis A. Breast cancers InterPro ID Mutated genes (number of mutations) IPR000219 ARHGEF4(2), ECT2(1), FARP1(1), FLJ20184(1), MCF2L2(1), NET1(1), OBSCN(5), RASGRF2(2), TRAD(1), VAV3(1) IPR000225 APC2(2), JUP(1), KPNA5(2), SPAG6(1) IPR000357 ARFGEF2(2), CMYA4(1), DRIM(2), JUP(1), KPNA5(2), PIK3R4(1), SPAG6(1) IPR000533 AKAP9(2), C10orf39(1), C20orf23(1), CUTL1(1), HOOK1(1), HOOK3(1), KTN1(2), LRRFIP1(3), MYH1(3), MYH9(2), NEF3(1), NF2(1), RSN(1), TAX1BP1(1), TPM4(1) IPR000694 ADAM12(3), ADAMTS19(1), APC2(2), APXL(1), ARID1B(1), BAT2(2), BAT3(1), BCAR1(1), BCL11A(2), BCORL1(1), C14orf155(3), C1orf2(1), C1QB(1), C6orf31(1), C7orf11(1), CD2(1), CENTD3(3), CHD5(3), CIC(3), CMYA1(2), COL11A1(3), COL19A1(2), COL7A1(3), DAZAP1(1), DBN1(3), DVL3(1), EIF5(1), FAM44A(1), FAM47B(1), FHOD1(1), FLJ20584(1), G3BP2(2), GAB1(2), GGA3(1), GLI1(3), GPNMB(2), GRIN2D(3), HCN3(1), HOXA3(2), HOXA4(1), IRS4(1), KCNA5(1), KCNC2(1), LIP8(1), LOC374955(1), MAGEE1(2), MICAL1(2), MICAL‐L1(1), MLLT2(1), MMP15(1), N4BP2(1), NCOA6(2), NHS(1), NUP214(3), ODZ1(3), PER1(2), PER2(1), PHC1(1), PLXNB1(1), PPM1E(2), RAI17(2), RAPH1(2), RBAF600(2), SCARF2(1), SEMA4G(1), SLC16A2(1), SORBS1(1), SPEN(2), SPG4(1), TBX1(1), TCF1(2), TCF7L1(1), TESK1(1), THG‐1(1), TP53(18), TRIF(1), ZBTB3(2), ZNF318(2) IPR000909 CENTB1(2), PLCB1(1), PLCG1(1) IPR000998 AEGP(3), EGFL6(2), PRSS7(1) IPR001140 ABCB10(2), ABCB6(1), ABCB8(2) IPR001164 ARFGAP3(1), CENTB1(2), CENTD3(3), CENTG1(2) IPR001589 -
Rare Gene Deletions in Genetic Generalized and Rolandic Epilepsies
RESEARCH ARTICLE Rare gene deletions in genetic generalized and Rolandic epilepsies Kamel Jabbari1,2☯, Dheeraj R. Bobbili3☯, Dennis Lal1,4,5,6, Eva M. Reinthaler7, Julian Schubert8, Stefan Wolking8, Vishal Sinha9, Susanne Motameny1, Holger Thiele1, Amit Kawalia1, Janine AltmuÈ ller1,10, Mohammad Reza Toliat1, Robert Kraaij11, Jeroen van Rooij11, Andre G. Uitterlinden11, M. Arfan Ikram12, EuroEPINOMICS CoGIE Consortium¶, Federico Zara13, Anna-Elina Lehesjoki14,15, Roland Krause3, Fritz Zimprich7, Thomas Sander1, Bernd A. Neubauer16, Patrick May3, Holger Lerche8, Peter NuÈrnberg1,17,18* a1111111111 1 Cologne Center for Genomics, University of Cologne, Cologne, Germany, 2 Cologne Biocenter, Institute a1111111111 for Genetics, University of Cologne, Cologne, Germany, 3 Luxembourg Centre for Systems Biomedicine, a1111111111 University of Luxembourg, Esch-sur-Alzette, Luxembourg, 4 Psychiatric and Neurodevelopmental Genetics a1111111111 Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of a1111111111 America, 5 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, 6 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, 7 Department of Neurology, Medical University of Vienna, Vienna, Austria, 8 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of TuÈbingen, TuÈbingen, Germany, 9 Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland, 10 Institute of Human Genetics, University of Cologne, OPEN ACCESS Cologne, Germany, 11 Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands, 12 Departments of Epidemiology, Neurology, and Radiology, Erasmus Medical Center, Citation: Jabbari K, Bobbili DR, Lal D, Reinthaler Rotterdam, The Netherlands, 13 Laboratory of Neurogenetics and Neuroscience, Institute G. -
Whole Genome Sequencing Puts Forward Hypotheses on Metastasis Evolution and Therapy in Colorectal Cancer
ARTICLE DOI: 10.1038/s41467-018-07041-z OPEN Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer Naveed Ishaque1,2,3, Mohammed L. Abba4,5, Christine Hauser4,5, Nitin Patil4,5, Nagarajan Paramasivam3,6, Daniel Huebschmann 3, Jörg Hendrik Leupold4,5, Gnana Prakash Balasubramanian2, Kortine Kleinheinz 3, Umut H. Toprak3, Barbara Hutter 2, Axel Benner7, Anna Shavinskaya4, Chan Zhou4,5, Zuguang Gu1,3, Jules Kerssemakers 3, Alexander Marx8, Marcin Moniuszko9, Miroslaw Kozlowski9, Joanna Reszec9, Jacek Niklinski9, Jürgen Eils3, Matthias Schlesner 3,10, Roland Eils 1,3,11, Benedikt Brors 2,12 & 1234567890():,; Heike Allgayer 4,5 Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14,3’ UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis- specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3’ UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy. -
Perkinelmer Genomics to Request the Saliva Swab Collection Kit for Patients That Cannot Provide a Blood Sample As Whole Blood Is the Preferred Sample
Autism and Intellectual Disability TRIO Panel Test Code TR002 Test Summary This test analyzes 2429 genes that have been associated with Autism and Intellectual Disability and/or disorders associated with Autism and Intellectual Disability with the analysis being performed as a TRIO Turn-Around-Time (TAT)* 3 - 5 weeks Acceptable Sample Types Whole Blood (EDTA) (Preferred sample type) DNA, Isolated Dried Blood Spots Saliva Acceptable Billing Types Self (patient) Payment Institutional Billing Commercial Insurance Indications for Testing Comprehensive test for patients with intellectual disability or global developmental delays (Moeschler et al 2014 PMID: 25157020). Comprehensive test for individuals with multiple congenital anomalies (Miller et al. 2010 PMID 20466091). Patients with autism/autism spectrum disorders (ASDs). Suspected autosomal recessive condition due to close familial relations Previously negative karyotyping and/or chromosomal microarray results. Test Description This panel analyzes 2429 genes that have been associated with Autism and ID and/or disorders associated with Autism and ID. Both sequencing and deletion/duplication (CNV) analysis will be performed on the coding regions of all genes included (unless otherwise marked). All analysis is performed utilizing Next Generation Sequencing (NGS) technology. CNV analysis is designed to detect the majority of deletions and duplications of three exons or greater in size. Smaller CNV events may also be detected and reported, but additional follow-up testing is recommended if a smaller CNV is suspected. All variants are classified according to ACMG guidelines. Condition Description Autism Spectrum Disorder (ASD) refers to a group of developmental disabilities that are typically associated with challenges of varying severity in the areas of social interaction, communication, and repetitive/restricted behaviors. -
Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: from Brain to Behavior
Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: From Brain to Behavior Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) dem Fachbereich Psychologie der Philipps-Universität Marburg vorgelegt von Ayşe Özge Sungur aus Trabzon, Türkei Marburg, 2017 Vom Fachbereich Psychologie der Philipps-Universität Marburg als Dissertation am 27.09.2017 angenommen. Erstgutachter: Dr. Markus Wöhr, Philipps-Universität Marburg Zweitgutachter: Prof. Dr. Sören Krach, Universität zu Lübeck Tag der mündlichen Prüfung: 27.09.2017 i TABLE OF CONTENTS SUMMARY 1 ZUSAMMENFASSUNG 2 1 INTRODUCTION 3 1.1 Autism Spectrum Disorder ..................................................................................................... 3 1.1.1 Genetics of ASD ............................................................................................................ 6 1.1.2 Synaptic Pathways and ASD ......................................................................................... 9 1.2 SHANK Family of Proteins .................................................................................................. 11 1.2.1 Shankopathies in ASD ................................................................................................. 13 1.3 Animal Models of ASD ........................................................................................................ 15 1.3.1 Testing ASD in Animal Models .................................................................................. 15 Social interaction -
Protein Family Members. the GENE.FAMILY
Table 3: Protein family members. The GENE.FAMILY col- umn shows the gene family name defined either by HGNC (superscript `H', http://www.genenames.org/cgi-bin/family_ search) or curated manually by us from Entrez IDs in the NCBI database (superscript `C' for `Custom') that we have identified as corresonding for each ENTITY.ID. The members of each gene fam- ily that are in at least one of our synaptic proteome datasets are shown in IN.SYNAPSE, whereas those not found in any datasets are in the column OUT.SYNAPSE. In some cases the intersection of two HGNC gene families are needed to specify the membership of our protein family; this is indicated by concatenation of the names with an ampersand. ENTITY.ID GENE.FAMILY IN.SYNAPSE OUT.SYNAPSE AC Adenylate cyclasesH ADCY1, ADCY2, ADCY10, ADCY4, ADCY3, ADCY5, ADCY7 ADCY6, ADCY8, ADCY9 actin ActinsH ACTA1, ACTA2, ACTB, ACTC1, ACTG1, ACTG2 ACTN ActininsH ACTN1, ACTN2, ACTN3, ACTN4 AKAP A-kinase anchoring ACBD3, AKAP1, AKAP11, AKAP14, proteinsH AKAP10, AKAP12, AKAP17A, AKAP17BP, AKAP13, AKAP2, AKAP3, AKAP4, AKAP5, AKAP6, AKAP8, CBFA2T3, AKAP7, AKAP9, RAB32 ARFGEF2, CMYA5, EZR, MAP2, MYO7A, MYRIP, NBEA, NF2, SPHKAP, SYNM, WASF1 CaM Endogenous ligands & CALM1, CALM2, EF-hand domain CALM3 containingH CaMKK calcium/calmodulin- CAMKK1, CAMKK2 dependent protein kinase kinaseC CB CalbindinC CALB1, CALB2 CK1 Casein kinase 1C CSNK1A1, CSNK1D, CSNK1E, CSNK1G1, CSNK1G2, CSNK1G3 CRHR Corticotropin releasing CRHR1, CRHR2 hormone receptorsH DAGL Diacylglycerol lipaseC DAGLA, DAGLB DGK Diacylglycerol kinasesH DGKB, -
Synaptic Pathways Related to Shank3 and Its Interaction Partner Prosapip1
International Graduate School in Molecular Medicine Ulm International PhD Programme in Molecular Medicine Synaptic pathways related to Shank3 and its interaction partner ProSAPiP1 Dissertation submitted in partial fulfilment of the requirements for the degree of „Doctor rerum naturalium” (Dr. rer. nat.) of the International Graduate School in Molecular Medicine Ulm Dominik Reim Born in Nürtingen, Germany Institute for Anatomy and Cell Biology, Head: Prof. Dr. Tobias M. Böckers 2016 1. Current dean / chairman of the Graduate School: Prof. Dr. Michael Kühl 2. Thesis Advisory Committee: - First supervisor: Prof. Dr. Tobias M. Böckers - Second supervisor: Prof. Dr. Thomas Wirth - Third supervisor: Dr. Chiara Verpelli 3. External reviewer: Prof. Dr. Matthias Kneussel 4. Day doctorate awarded: March 20, 2017 Results gained in my thesis have previously been published in the following publications: Reim, D., Distler, U., Halbedl, S., Verpelli, C., Sala, C., Bockmann, J., Tenzer, S., Boeckers, T.M., and Schmeisser, M.J. (2017). Proteomic analysis of postsynaptic density fractions from Shank3 mutant mice reveals brain region specific changes relevant to autism spectrum disorder. Front Mol Neurosci, doi: 10.3389/fnmol.2017.00026 Reim, D., Weis, T.M., Halbedl, S., Delling, J.P., Grabrucker, A.M., Boeckers, T.M., and Schmeisser, M.J. (2016). The Shank3 Interaction Partner ProSAPiP1 Regulates Postsynaptic SPAR Levels and the Maturation of Dendritic Spines in Hippocampal Neurons. Front Synaptic Neurosci 8, 13, doi: 10.3389/fnsyn.2016.00013 Vicidomini, C., Ponzoni, L., Lim, D., Schmeisser, M.J., Reim, D., Morello, N., Orellana, D., Tozzi, A., Durante, V., Scalmani, P., Mantegazza, M., Genazzani, A.A., Giustetto, M., Sala, M., Calabresi, P., Boeckers, T.M., Sala, C., and Verpelli, C. -
Using Gene Ontology to Describe the Role of the Neurexin-Neuroligin-SHANK Complex in Human, Mouse and Rat and Its Relevance to Autism Patel Et Al
Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism Patel et al. Patel et al. BMC Bioinformatics (2015) 16:186 DOI 10.1186/s12859-015-0622-0 Patel et al. BMC Bioinformatics (2015) 16:186 DOI 10.1186/s12859-015-0622-0 METHODOLOGY ARTICLE Open Access Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism Sejal Patel1,2,3, Paola Roncaglia4,5 and Ruth C. Lovering3* Abstract Background: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders. Results: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database. Conclusions: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained throughgenomewideassociationstudies, next generation sequencing, proteomic and transcriptomic datasets. -
Towards a Gene-Level Map of Resilience to Genetic Variants Associated with Autism Thomas Rolland1*, Freddy Cliquet1, Richard
medRxiv preprint doi: https://doi.org/10.1101/2021.02.12.21251621; this version posted February 13, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Rolland et al. Towards a gene-level map of resilience to geneticperpetuity. variants associated with autism It is made available under a CC-BY-NC 4.0 International license . Towards a gene-level map of resilience to genetic variants associated with autism Thomas Rolland1*, Freddy Cliquet1, Richard J.L. Anney2, Nicolas Traut1,3, Alexandre Mathieu1, Guillaume Huguet4,5, Claire S. Leblond1, Elise Douard4,5, Frédérique Amsellem1,6, Simon Malesys1, Anna Maruani1,6, Roberto Toro1,3, Alan Packer7, Wendy K. Chung7,8, Sébastien Jacquemont4,5, Richard Delorme1,6, Thomas Bourgeron1* 1 Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France 2 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, CF24 4HQ, UK 3 Center for Research and Interdisciplinarity (CRI), Université Paris Descartes, Paris, France 4 Department of Pediatrics, Université de Montréal, Montreal, QC, Canada 5 Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, QC, Canada 6 Department of Child and Adolescent Psychiatry, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France 7 Simons Foundation, New York, NY, USA. 8 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. * e-mail: [email protected] , [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. -
SHANK1 Deletions in Males with Autism Spectrum Disorder
Please cite this article in press as: Sato et al., SHANK1 Deletions in Males with Autism Spectrum Disorder, The American Journal of Human Genetics (2012), doi:10.1016/j.ajhg.2012.03.017 REPORT SHANK1 Deletions in Males with Autism Spectrum Disorder Daisuke Sato,1 Anath C. Lionel,1,2 Claire S. Leblond,3,4,5 Aparna Prasad,1 Dalila Pinto,1 Susan Walker,1 Irene O’Connor,6 Carolyn Russell,6 Irene E. Drmic,7 Fadi F. Hamdan,8 Jacques L. Michaud,8 Volker Endris,9 Ralph Roeth,9 Richard Delorme,3,4,5,10 Guillaume Huguet,3,4,5 Marion Leboyer,11,12 Maria Rastam,13 Christopher Gillberg,14,15 Mark Lathrop,16 Dimitri J. Stavropoulos,17 Evdokia Anagnostou,18 Rosanna Weksberg,19 Eric Fombonne,20 Lonnie Zwaigenbaum,21 Bridget A. Fernandez,22 Wendy Roberts,7,18 Gudrun A. Rappold,9 Christian R. Marshall,1,2 Thomas Bourgeron,3,4,5 Peter Szatmari,6,* and Stephen W. Scherer1,2,* Recent studies have highlighted the involvement of rare (<1% frequency) copy-number variations and point mutations in the genetic etiology of autism spectrum disorder (ASD); these variants particularly affect genes involved in the neuronal synaptic complex. The SHANK gene family consists of three members (SHANK1, SHANK2, and SHANK3), which encode scaffolding proteins required for the proper formation and function of neuronal synapses. Although SHANK2 and SHANK3 mutations have been implicated in ASD and intellectual disability, the involvement of SHANK1 is unknown. Here, we assess microarray data from 1,158 Canadian and 456 European individuals with ASD to discover microdeletions at the SHANK1 locus on chromosome 19. -
Exploratory Neuroimmune Profiling Identifies CNS-Specific Alterations in COVID-19 Patients with Neurological Involvement
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.11.293464; this version posted December 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Exploratory neuroimmune profiling identifies CNS-specific alterations in COVID-19 patients with neurological involvement Authors: Eric Song1,†,*, Christopher M. Bartley2,3,4†, Ryan D. Chow5, Thomas T. Ngo3,4, Ruoyi Jiang1, Colin R. Zamecnik3,6, Ravi Dandekar3,6, Rita P. Loudermilk3,6, Yile Dai1, Feimei Liu1, Isobel A. Hawes3,6,7, Bonny D. Alvarenga3,6, Trung Huynh3,6, Lindsay McAlpine8, Nur-Taz Rahman9, Bertie Geng10, Jennifer Chiarella8, Benjamin Goldman-Israelow1,9, Chantal B.F. Vogels11, Nathan D. Grubaugh11, Arnau Casanovas-Massana11, Brett S. Phinney12, Michelle Salemi12, Jessa Alexander3,6, Juan A. Gallego13-15, Todd Lencz13-15, Hannah Walsh9, Carolina Lucas1, Jon Klein1, Tianyang Mao1, Jieun Oh1, Aaron Ring1, Serena Spudich8, Albert I. Ko10,11, Steven H. Kleinstein1,16,17, Joseph L. DeRisi18,19, Akiko Iwasaki1,20,21, Samuel J. Pleasure3,6,b Michael R. Wilson3,6, ‡,*, Shelli F. Farhadian8,10, ‡,* Affiliations: 1 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. 2 Hanna H. Gray Fellow, Howard Hughes Medical Institute, Chevy Chase, MD, USA. 3 Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. 4 Department of Psychiatry, University of California, San Francisco, CA, USA. 5 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.