Identification and Characterization of Asymmetrically-Expressed Genes

Summary

Principal Investigator: Daniel H Geschwind
Abstract: One of the most important functional specializations of the human cerebral cortex is that of the perisylvian cortex and the other subcortical regions with which it is connected. These regions are involved in human higher cognition and behavior, including language. Surprisingly little is known about the biological processes that underlie the development of perisylvian cortical regions in humans, their asymmetry, and presence in other potential model organisms. This proposal is an extension of the Pi's Merit Award, in which we have worked successfully to identify key genes involved in human higher cognition by virtue of their asymmetric expression or enrichment in perisylvian cortex, including CNTNAP2 and other extracellular adhesion molecules that are also related to neuropsychlatric disease. In parallel, we have developed an entirely novel approach to elucidate the complex structure of the transcriptome, and successfully applied this to adult human brain. We propose to apply these methods in conjunction with NextGen sequencing to perform digital gene expression in anatomically defined interconnected human language cortex and its homologues in nonhuman primates. This work will put gene products in a clear functional context, enabling characterization of the set of genes most central to this aspect of human brain organization, rather than relying on less structured means of prioritizing genes for follow-up. Putative differentially expressed genes and key hub genes within the networks will be confirmed using qRT-PCR and In Situ hybridization. Cross species comparisons, in mice and non-human primate species will continue to be performed to investigate the evolutionary conservation of genes that are central hubs of the modules that are enriched in languagerelated cortex in adults, or asymmetrically expressed in the developing human cerebral cortex. This will provide insight into the potential role of these genes in the development and evolution of language and related human cognitive specializations and the relationship of these regions in lower species to homologous human structures. All of this will clearly inform the study of human neurodevelopmental disorders that are related to speech and language, such as autism or schizoprenia, as we and others have already demonstrated, and provide proper context for the use of animal models for these disorders.
Funding Period: 1999-07-10 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Advances in autism genetics: on the threshold of a new neurobiology
    Brett S Abrahams
    Neurology Department, and Semel Institute for Neuroscience and Behaviour, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095 1769 USA
    Nat Rev Genet 9:341-55. 2008
  2. pmc Transcriptomic analysis of autistic brain reveals convergent molecular pathology
    Irina Voineagu
    Program in Neurogenetics and Neurobehavioral Genetics, Department of Neurology and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095 1769, USA
    Nature 474:380-4. 2011
  3. pmc Modeling the functional genomics of autism using human neurons
    G Konopka
    Department of Neurology, Center for Autism Research and Treatment, Semel Institute and Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Mol Psychiatry 17:202-14. 2012
  4. pmc Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk
    Zohar Mukamel
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    J Neurosci 31:11437-42. 2011
  5. pmc Genetics of autism spectrum disorders
    Daniel H Geschwind
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Trends Cogn Sci 15:409-16. 2011
  6. pmc Transcriptional architecture of the primate neocortex
    Amy Bernard
    Allen Institute for Brain Science, Seattle, WA 98103, USA
    Neuron 73:1083-99. 2012
  7. pmc RBFOX1 regulates both splicing and transcriptional networks in human neuronal development
    Brent L Fogel
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
    Hum Mol Genet 21:4171-86. 2012
  8. pmc Human-specific transcriptional networks in the brain
    Genevieve Konopka
    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
    Neuron 75:601-17. 2012
  9. pmc Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution
    Jia Zeng
    School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA
    Am J Hum Genet 91:455-65. 2012
  10. pmc Cortical evolution: judge the brain by its cover
    Daniel H Geschwind
    Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA, 90095, USA Electronic address
    Neuron 80:633-47. 2013

Research Grants

  1. Axon Guidance in the Olfactory System
    DIEGO JAVIER RODRIGUEZ-GIL; Fiscal Year: 2013
  2. Mechanisms of Central Neuron Synaptogenesis
    ANN M CRAIG; Fiscal Year: 2013
  3. MR Brain Diffusion Tensor Imaging in Schizophrenia
    Martha E Shenton; Fiscal Year: 2013
  4. A neuroimaging study of twin pairs with autism
    ANTONIO YOUSSEF HARDAN; Fiscal Year: 2013
  5. The Role of Astrocytes in Cortical Interneuron Development
    KAREN MULLER SMITH; Fiscal Year: 2013
  6. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
  7. DETERMINATION OF NEURONAL FATES IN VISUAL CORTEX
    Susan K McConnell; Fiscal Year: 2013
  8. FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions
    Genevieve Konopka; Fiscal Year: 2013
  9. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
  10. Adapting Cognitive Enhancement Therapy for ASD
    Nancy J Minshew; Fiscal Year: 2013

Detail Information

Publications24

  1. pmc Advances in autism genetics: on the threshold of a new neurobiology
    Brett S Abrahams
    Neurology Department, and Semel Institute for Neuroscience and Behaviour, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095 1769 USA
    Nat Rev Genet 9:341-55. 2008
    ..Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme...
  2. pmc Transcriptomic analysis of autistic brain reveals convergent molecular pathology
    Irina Voineagu
    Program in Neurogenetics and Neurobehavioral Genetics, Department of Neurology and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095 1769, USA
    Nature 474:380-4. 2011
    ..Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder...
  3. pmc Modeling the functional genomics of autism using human neurons
    G Konopka
    Department of Neurology, Center for Autism Research and Treatment, Semel Institute and Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Mol Psychiatry 17:202-14. 2012
    ..These data also provide a step towards better understanding of the signaling pathways disrupted in ASD...
  4. pmc Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk
    Zohar Mukamel
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    J Neurosci 31:11437-42. 2011
    ..The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk...
  5. pmc Genetics of autism spectrum disorders
    Daniel H Geschwind
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Trends Cogn Sci 15:409-16. 2011
    ....
  6. pmc Transcriptional architecture of the primate neocortex
    Amy Bernard
    Allen Institute for Brain Science, Seattle, WA 98103, USA
    Neuron 73:1083-99. 2012
    ..These data provide a unique resource detailing neocortical transcription patterns in a nonhuman primate with great similarity in gene expression to human...
  7. pmc RBFOX1 regulates both splicing and transcriptional networks in human neuronal development
    Brent L Fogel
    Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
    Hum Mol Genet 21:4171-86. 2012
    ....
  8. pmc Human-specific transcriptional networks in the brain
    Genevieve Konopka
    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
    Neuron 75:601-17. 2012
    ..These data demonstrate that transcriptional networks have undergone evolutionary remodeling even within a given brain region, providing a window through which to view the foundation of uniquely human cognitive capacities...
  9. pmc Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution
    Jia Zeng
    School of Biology, Georgia Institute of Technology, Atlanta, GA 30332, USA
    Am J Hum Genet 91:455-65. 2012
    ..Thus, comparative studies of humans and chimpanzees stand to identify key epigenomic modifications underlying the evolution of human-specific traits...
  10. pmc Cortical evolution: judge the brain by its cover
    Daniel H Geschwind
    Program in Neurogenetics, Department of Neurology, University of California, Los Angeles, Los Angeles, CA, 90095, USA Electronic address
    Neuron 80:633-47. 2013
    ..This knowledge provides essential insight into the pathogenesis of human-specific neuropsychiatric disorders...
  11. pmc Human brain evolution: harnessing the genomics (r)evolution to link genes, cognition, and behavior
    Genevieve Konopka
    Department of Neurology, University of California, Los Angeles, Los Angeles, CA 90095, USA
    Neuron 68:231-44. 2010
    ..Furthermore, these integrative approaches should provide important insights into human diseases...
  12. pmc Explaining human uniqueness: genome interactions with environment, behaviour and culture
    Ajit Varki
    Center for Academic Research and Training in Anthropogeny, University of California, San Diego, La Jolla, California 92093, USA
    Nat Rev Genet 9:749-63. 2008
    ....
  13. pmc Functional organization of the transcriptome in human brain
    Michael C Oldham
    Interdepartmental Program for Neuroscience, University of California Los Angeles, Los Angeles, California 90095, USA
    Nat Neurosci 11:1271-82. 2008
    ..Our findings provide a new foundation for neurogenetic inquiries by revealing a robust and previously unrecognized organization to the human brain transcriptome...
  14. pmc Autism: many genes, common pathways?
    Daniel H Geschwind
    Neurogenetics Program, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Cell 135:391-5. 2008
    ..Unifying principles among cases of autism are likely to be at the level of brain circuitry in addition to molecular pathways...
  15. pmc A functional genetic link between distinct developmental language disorders
    Sonja C Vernes
    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    N Engl J Med 359:2337-45. 2008
    ..Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment...
  16. pmc Endogenous Wnt signaling maintains neural progenitor cell potency
    Eric M Wexler
    Department of Psychiatry, The Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA 90024 1759, USA
    Stem Cells 27:1130-41. 2009
    ..In sum, this study establishes that autonomous Wnt signaling is a conserved feature of the neurogenic niche that preserves the delicate balance between NSC maintenance and differentiation...
  17. pmc The organization of the transcriptional network in specific neuronal classes
    Kellen D Winden
    Interdepartmental Program for Neuroscience, University of California Los Angeles, Los Angeles, CA, USA
    Mol Syst Biol 5:291. 2009
    ..These analyses provide a basis for understanding how specific aspects of neuronal phenotypic diversity are organized at the transcriptional level...
  18. pmc Neuroscience in the era of functional genomics and systems biology
    Daniel H Geschwind
    Program in Neurogenetics and Neurobehavioural Genetics, Department of Neurology and Semel Institute, David Geffen School of Medicine, Los Angeles, California 90095, USA
    Nature 461:908-15. 2009
    ..Methods for network analysis and systems biology offer the promise of integrating these multiple levels of data, connecting molecular pathways to nervous system function...
  19. pmc Human-specific transcriptional regulation of CNS development genes by FOXP2
    Genevieve Konopka
    Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    Nature 462:213-7. 2009
    ..Because FOXP2 has an important role in speech and language in humans, the identified targets may have a critical function in the development and evolution of language circuitry in humans...
  20. pmc Connecting genes to brain in the autism spectrum disorders
    Brett S Abrahams
    Neurogenetics Program, Neurology Department, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095 1769, USA
    Arch Neurol 67:395-9. 2010
    ..Understanding genetic data within an anatomical context will be critical to explain how individual risk factors operate to shape phenotypic presentation in patients...
  21. pmc Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathways
    Jeremy A Miller
    Interdepartmental Program for Neuroscience, Department of Human Genetics and Biostatistics, University of California, Los Angeles, CA 90095 1769, USA
    Proc Natl Acad Sci U S A 107:12698-703. 2010
    ..Together, this work identifies convergent and divergent pathways in mouse and human, and provides a systematic framework that will be useful for understanding the applicability of mouse models for human brain disorders...
  22. pmc Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism
    Neelroop N Parikshak
    Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA Interdepartmental Program in Neuroscience, University of California, Los Angeles, Los Angeles, CA 90095, USA
    Cell 155:1008-21. 2013
    ..Furthermore, we show that the patterns of ASD and ID risk genes are distinct, providing a biological framework for further investigating the pathophysiology of ASD. ..

Research Grants30

  1. Axon Guidance in the Olfactory System
    DIEGO JAVIER RODRIGUEZ-GIL; Fiscal Year: 2013
    ....
  2. Mechanisms of Central Neuron Synaptogenesis
    ANN M CRAIG; Fiscal Year: 2013
    ....
  3. MR Brain Diffusion Tensor Imaging in Schizophrenia
    Martha E Shenton; Fiscal Year: 2013
    ..This proposal will lead to new findings regarding WM abnormalities and cognitive and clinical correlates, which, in turn, will ultimately lead to better and more rationale treatment of this devastating disorder. ..
  4. A neuroimaging study of twin pairs with autism
    ANTONIO YOUSSEF HARDAN; Fiscal Year: 2013
    ..A better understanding of the pathophysiology of autism will be instrumental in the development of effective therapeutic strategies that aim at targeting the core symptoms of social and communication deficits. ..
  5. The Role of Astrocytes in Cortical Interneuron Development
    KAREN MULLER SMITH; Fiscal Year: 2013
    ..The ultimate goal of this research is to identify mechanisms that contribute to interneuron maturation and survival, possibly leading to novel therapies aimed at preventing or reversing interneuron disruption in psychiatric illnesses. ..
  6. EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATH
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  7. DETERMINATION OF NEURONAL FATES IN VISUAL CORTEX
    Susan K McConnell; Fiscal Year: 2013
    ..The goals of our research are to identify the genes that regulate neurogenesis in the visual cortex and to understand how they affect the formation of cortical circuitry. ..
  8. FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive Functions
    Genevieve Konopka; Fiscal Year: 2013
    ..abstract_text> ..
  9. Emory Alzheimer's Disease Center
    Allan I Levey; Fiscal Year: 2013
    ..abstract_text> ..
  10. Adapting Cognitive Enhancement Therapy for ASD
    Nancy J Minshew; Fiscal Year: 2013
    ....
  11. Novel Ad/MVA and Ad/Protein HIV-1 Vaccines
    Dan H Barouch; Fiscal Year: 2013
    ..To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys. ..
  12. Development and Organization of the Human Frontal Cortex
    Nenad Sestan; Fiscal Year: 2013
    ..Just as importantly, our studies will survey a comprehensive selection of brain regions for high spatial resolution of gene expression mapping, especially within the frontal lobe. ..
  13. Maternal and Child Health in Poor Countries: Evidence from Randomized Evaluations
    ESTHER DUFLO; Fiscal Year: 2013
    ..It will compare the impact of this program with that of a government program that gives women financial incentives for institutional delivery. ..