Identification and Characterization of Asymmetrically-Expressed Genes
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
- Advances in autism genetics: on the threshold of a new neurobiologyBrett 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...
- Transcriptomic analysis of autistic brain reveals convergent molecular pathologyIrina 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...
- Modeling the functional genomics of autism using human neuronsG 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...
- Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism riskZohar 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...
- Genetics of autism spectrum disordersDaniel 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....
- Transcriptional architecture of the primate neocortexAmy 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...
- RBFOX1 regulates both splicing and transcriptional networks in human neuronal developmentBrent 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....
- Human-specific transcriptional networks in the brainGenevieve 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...
- Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolutionJia 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...
- Cortical evolution: judge the brain by its coverDaniel 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...
- Human brain evolution: harnessing the genomics (r)evolution to link genes, cognition, and behaviorGenevieve 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...
- Explaining human uniqueness: genome interactions with environment, behaviour and cultureAjit 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....
- Functional organization of the transcriptome in human brainMichael 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...
- 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...
- A functional genetic link between distinct developmental language disordersSonja 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...
- Endogenous Wnt signaling maintains neural progenitor cell potencyEric 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...
- The organization of the transcriptional network in specific neuronal classesKellen 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...
- Neuroscience in the era of functional genomics and systems biologyDaniel 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...
- Human-specific transcriptional regulation of CNS development genes by FOXP2Genevieve 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...
- Connecting genes to brain in the autism spectrum disordersBrett 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...
- Divergence of human and mouse brain transcriptome highlights Alzheimer disease pathwaysJeremy 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...
- Integrative functional genomic analyses implicate specific molecular pathways and circuits in autismNeelroop 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. ..
- Axon Guidance in the Olfactory SystemDIEGO JAVIER RODRIGUEZ-GIL; Fiscal Year: 2013....
- Mechanisms of Central Neuron SynaptogenesisANN M CRAIG; Fiscal Year: 2013....
- MR Brain Diffusion Tensor Imaging in SchizophreniaMartha 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. ..
- A neuroimaging study of twin pairs with autismANTONIO 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. ..
- The Role of Astrocytes in Cortical Interneuron DevelopmentKAREN 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. ..
- EARLY INDICATORS OF LATER WORK LEVELS, DISEASE AND DEATHDora L Costa; Fiscal Year: 2013..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
- DETERMINATION OF NEURONAL FATES IN VISUAL CORTEXSusan 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. ..
- FOXP2-Regulated Signaling Pathways Critical for Higher Cognitive FunctionsGenevieve Konopka; Fiscal Year: 2013..abstract_text> ..
- Emory Alzheimer's Disease CenterAllan I Levey; Fiscal Year: 2013..abstract_text> ..
- Adapting Cognitive Enhancement Therapy for ASDNancy J Minshew; Fiscal Year: 2013....
- Novel Ad/MVA and Ad/Protein HIV-1 VaccinesDan 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. ..
- Development and Organization of the Human Frontal CortexNenad 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. ..
- Maternal and Child Health in Poor Countries: Evidence from Randomized EvaluationsESTHER 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. ..