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1. Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability

Author

Bae, Taejeong, Fasching, Liana, Wang, Yifan, Shin, Joo Heon, Suvakov, Milovan, Jang, Yeongjun, Norton, Scott, Dias, Caroline, Mariani, Jessica, Jourdon, Alexandre, Wu, Feinan, Panda, Arijit, Pattni, Reenal, Chahine, Yasmine, Yeh, Rebecca, Roberts, Rosalinda C, Huttner, Anita, Kleinman, Joel E, Hyde, Thomas M, Straub, Richard E, Walsh, Christopher A, Urban, Alexander E, Leckman, James F, Weinberger, Daniel R, Vaccarino, Flora M, Abyzov, Alexej, Park, Peter J, Sestan, Nenad, Weinberger, Daniel, Moran, John V, Gage, Fred H, Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Chess, Andrew J, Akbarian, Schahram, Bizzotto, Sara, Coulter, Michael, D’Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lee, Alice, Lodato, Michael, Maury, Eduardo A, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Sherman, Maxwell, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Molitor, Cindy, Peters, Mette, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Serres Amero, Aitor, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Solis Moruno, Manuel, Garcia Perez, Raquel, Povolotskaya, Inna, Soriano, Eduardo, Antaki, Danny, and Averbuj, Dan

Subjects
Biotechnology, Brain Disorders, Intellectual and Developmental Disabilities (IDD), Genetics, Autism, Pediatric, Mental Health, Human Genome, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Mental health, Aging, Autistic Disorder, Brain, Enhancer Elements, Genetic, Gene Expression Regulation, Humans, Mutagenesis, Mutation, Protein Binding, Transcription Factors, Whole Genome Sequencing, Brain Somatic Mosaicism Network§, General Science & Technology
Abstract

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

Published
2022

4. Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A, Jones, Attila G, Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L, Bizzotto, Sara, Emery, Sarah B, Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J, Moldovan, John B, Narurkar, Rujuta, Oetjens, Matthew T, Rodin, Rachel E, Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E, Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G, Marquès-Bonet, Tomas, Park, Peter J, Peters, Mette A, Pevsner, Jonathan, Walsh, Christopher A, Weinberger, Daniel R, Vaccarino, Flora M, Moran, John V, Urban, Alexander E, Kidd, Jeffrey M, Mills, Ryan E, and Abyzov, Alexej

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Neurosciences, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Alleles, Brain, Chromosome Mapping, Computational Biology, Genetic Association Studies, Genetic Variation, Genomics, Germ Cells, High-Throughput Nucleotide Sequencing, Humans, Organ Specificity, Polymorphism, Single Nucleotide, Brain Somatic Mosaicism Network, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

BackgroundPost-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.ResultsHere, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees.ConclusionsThis study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

Published
2021

5. Landmarks of human embryonic development inscribed in somatic mutations

Author

Bizzotto, Sara, Dou, Yanmei, Ganz, Javier, Doan, Ryan N, Kwon, Minseok, Bohrson, Craig L, Kim, Sonia N, Bae, Taejeong, Abyzov, Alexej, Network†, NIMH Brain Somatic Mosaicism, Park, Peter J, and Walsh, Christopher A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, Pediatric, Biotechnology, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Adolescent, Adult, Cell Division, Cell Lineage, Clone Cells, Embryonic Development, Female, Gastrula, Gastrulation, Genetic Variation, Germ Layers, Humans, Male, Mutation, Neural Stem Cells, Neurons, Organogenesis, Polymorphism, Single Nucleotide, Prosencephalon, Single-Cell Analysis, Whole Genome Sequencing, NIMH Brain Somatic Mosaicism Network, General Science & Technology
Abstract

Although cell lineage information is fundamental to understanding organismal development, very little direct information is available for humans. We performed high-depth (250×) whole-genome sequencing of multiple tissues from three individuals to identify hundreds of somatic single-nucleotide variants (sSNVs). Using these variants as "endogenous barcodes" in single cells, we reconstructed early embryonic cell divisions. Targeted sequencing of clonal sSNVs in different organs (about 25,000×) and in more than 1000 cortical single cells, as well as single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing of ~100,000 cortical single cells, demonstrated asymmetric contributions of early progenitors to extraembryonic tissues, distinct germ layers, and organs. Our data suggest onset of gastrulation at an effective progenitor pool of about 170 cells and about 50 to 100 founders for the forebrain. Thus, mosaic mutations provide a permanent record of human embryonic development at very high resolution.

Published
2021

6. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Marshall, Christian R., Merico, Daniele, Thiruvahindrapuram, Bhooma, Wang, Zhouzhi, Scherer, Stephen W., Howrigan, Daniel P, Ripke, Stephan, Bulik-Sullivan, Brendan, Farh, Kai-How, Fromer, Menachem, Goldstein, Jacqueline I., Huang, Hailiang, Lee, Phil, Daly, Mark J., Neale, Benjamin M., Belliveau, Richard A., Jr., Bergen, Sarah E., Bevilacqua, Elizabeth, Chambert, Kimberley D., O'Dushlaine, Colm, Scolnick, Edward M., Smoller, Jordan W., Moran, Jennifer L., Palotie, Aarno, Petryshen, Tracey L., Wu, Wenting, Greer, Douglas S., Antaki, Danny, Shetty, Aniket, Gujral, Madhusudan, Brandler, William M., Malhotra, Dheeraj, Fuentes Fajarado, Karin V., Maile, Michelle S., Holmans, Peter A., Carrera, Noa, Craddock, Nick, Escott-Price, Valentina, Georgieva, Lyudmila, Hamshere, Marian L., Kavanagh, David, Legge, Sophie E., Pocklington, Andrew J., Richards, Alexander L., Ruderfer, Douglas M., Williams, Nigel M., Kirov, George, Owen, Michael J., Pinto, Dalila, Cai, Guiqing, Davis, Kenneth L., Drapeau, Elodie, Friedman, Joseph I, Haroutunian, Vahram, Parkhomenko, Elena, Reichenberg, Abraham, Silverman, Jeremy M., Buxbaum, Joseph D., Domenici, Enrico, Agartz, Ingrid, Djurovic, Srdjan, Mattingsdal, Morten, Melle, Ingrid, Andreassen, Ole A., Jönsson, Erik G., Söderman, Erik, Albus, Margot, Alexander, Madeline, Laurent, Claudine, Levinson, Douglas F., Amin, Farooq, Atkins, Joshua, Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Wu, Jing Qin, Bacanu, Silviu A., Bigdeli, Tim B., Reimers, Mark A., Webb, Bradley T., Wolen, Aaron R., Wormley, Brandon K., Kendler, Kenneth S., Riley, Brien P., Kähler, Anna K., Magnusson, Patrik K.E., Hultman, Christina M., Bertalan, Marcelo, Hansen, Thomas, Olsen, Line, Rasmussen, Henrik B., Werge, Thomas, Mattheisen, Manuel, Black, Donald W., Bruggeman, Richard, Buccola, Nancy G., Buckner, Randy L., Roffman, Joshua L., Byerley, William, Cahn, Wiepke, Kahn, René S, Strengman, Eric, Ophoff, Roel A., Carr, Vaughan J., Catts, Stanley V., Henskens, Frans A., Loughland, Carmel M., Michie, Patricia T., Pantelis, Christos, Schall, Ulrich, Jablensky, Assen V., Kelly, Brian J., Campion, Dominique, Cantor, Rita M., Cheng, Wei, Cloninger, C. Robert, Svrakic, Dragan M, Cohen, David, Cormican, Paul, Donohoe, Gary, Morris, Derek W., Corvin, Aiden, Gill, Michael, Crespo-Facorro, Benedicto, Crowley, James J., Farrell, Martilias S., Giusti-Rodríguez, Paola, Kim, Yunjung, Szatkiewicz, Jin P., Williams, Stephanie, Curtis, David, Pimm, Jonathan, Gurling, Hugh, McQuillin, Andrew, Davidson, Michael, Weiser, Mark, Degenhardt, Franziska, Forstner, Andreas J., Herms, Stefan, Hoffmann, Per, Hofman, Andrea, Cichon, Sven, Nöthen, Markus M., Del Favero, Jurgen, DeLisi, Lynn E., McCarley, Robert W., Levy, Deborah L., Mesholam-Gately, Raquelle I., Seidman, Larry J., Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Duan, Jubao, Sanders, Alan R., Gejman, Pablo V., Gershon, Elliot S., Dudbridge, Frank, Eichhammer, Peter, Eriksson, Johan, Salomaa, Veikko, Essioux, Laurent, Fanous, Ayman H., Knowles, James A., Pato, Michele T., Pato, Carlos N., Frank, Josef, Meier, Sandra, Schulze, Thomas G., Strohmaier, Jana, Witt, Stephanie H., Rietschel, Marcella, Franke, Lude, Karjalainen, Juha, Freedman, Robert, Olincy, Ann, Freimer, Nelson B., Purcell, Shaun M., Roussos, Panos, Stahl, Eli A., Sklar, Pamela, Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Godard, Stephanie, Hirschhorn, Joel N., Pers, Tune H., Price, Alkes, Esko, Tõnu, Gratten, Jacob, Lee, S. Hong, Visscher, Peter M., Wray, Naomi R., Mowry, Bryan J., de Haan, Lieuwe, Meijer, Carin J., Hansen, Mark, Ikeda, Masashi, Iwata, Nakao, Joa, Inge, Kalaydjieva, Luba, Keller, Matthew C., Kennedy, James L., Zai, Clement C., Knight, Jo, Lerer, Bernard, Liang, Kung-Yee, Lieberman, Jeffrey, Stroup, T. Scott, Lönnqvist, Jouko, Suvisaari, Jaana, Maher, Brion S., Maier, Wolfgang, Mallet, Jacques, McDonald, Colm, McIntosh, Andrew M., Blackwood, Douglas H.R., Metspalu, Andres, Milani, Lili, Milanova, Vihra, Mokrab, Younes, Collier, David A., Müller-Myhsok, Bertram, Murphy, Kieran C., Murray, Robin M., Powell, John, Myin-Germeys, Inez, Van Os, Jim, Nenadic, Igor, Nertney, Deborah A., Nestadt, Gerald, Pulver, Ann E., Nicodemus, Kristin K., Nisenbaum, Laura, Nordin, Annelie, Adolfsson, Rolf, O'Callaghan, Eadbhard, Oh, Sang-Yun, O'Neill, F. Anthony, Paunio, Tiina, Pietiläinen, Olli, Perkins, Diana O., Quested, Digby, Savitz, Adam, Li, Qingqin S., Schwab, Sibylle G., Shi, Jianxin, Spencer, Chris C.A., Thirumalai, Srinivas, Veijola, Juha, Waddington, John, Walsh, Dermot, Wildenauer, Dieter B., Bramon, Elvira, Darvasi, Ariel, Posthuma, Danielle, St. Clair, David, Shanta, Omar, Klein, Marieke, Park, Peter J., Weinberger, Daniel, Moran, John V., Gage, Fred H., Vaccarino, Flora M., Gleeson, Joseph, Mathern, Gary, Courchesne, Eric, Roy, Subhojit, Bizzotto, Sara, Coulter, Michael, Dias, Caroline, D'Gama, Alissa, Ganz, Javier, Hill, Robert, Huang, August Yue, Khoshkhoo, Sattar, Kim, Sonia, Lodato, Michael, Miller, Michael, Borges-Monroy, Rebeca, Rodin, Rachel, Zhou, Zinan, Bohrson, Craig, Chu, Chong, Cortes-Ciriano, Isidro, Dou, Yanmei, Galor, Alon, Gulhan, Doga, Kwon, Minseok, Luquette, Joe, Viswanadham, Vinay, Jones, Attila, Rosenbluh, Chaggai, Cho, Sean, Langmead, Ben, Thorpe, Jeremy, Erwin, Jennifer, Jaffe, Andrew, McConnell, Michael, Narurkar, Rujuta, Paquola, Apua, Shin, Jooheon, Straub, Richard, Abyzov, Alexej, Bae, Taejeong, Jang, Yeongjun, Wang, Yifan, Gage, Fred, Linker, Sara, Reed, Patrick, Wang, Meiyan, Urban, Alexander, Zhou, Bo, Zhu, Xiaowei, Pattni, Reenal, Amero, Aitor Serres, Juan, David, Lobon, Irene, Marques-Bonet, Tomas, Moruno, Manuel Solis, Perez, Raquel Garcia, Povolotskaya, Inna, Soriano, Eduardo, Averbuj, Dan, Ball, Laurel, Breuss, Martin, Yang, Xiaoxu, Chung, Changuk, Emery, Sarah B., Flasch, Diane A., Kidd, Jeffrey M., Kopera, Huira C., Kwan, Kenneth Y., Mills, Ryan E., Moldovan, John B., Sun, Chen, Zhao, Xuefang, Zhou, Weichen, Frisbie, Trenton J., Cherskov, Adriana, Fasching, Liana, Jourdon, Alexandre, Pochareddy, Sirisha, Scuderi, Soraya, Sestan, Nenad, Maury, Eduardo A., Sherman, Maxwell A., Genovese, Giulio, Gilgenast, Thomas G., Kamath, Tushar, Burris, S.J., Rajarajan, Prashanth, Flaherty, Erin, Akbarian, Schahram, Chess, Andrew, McCarroll, Steven A., Loh, Po-Ru, Phillips-Cremins, Jennifer E., Brennand, Kristen J., Macosko, Evan Z., Walters, James T.R., O’Donovan, Michael, Sullivan, Patrick, Sebat, Jonathan, Lee, Eunjung A., and Walsh, Christopher A.

Published
2023
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7. Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements

Author

Luquette, Lovelace J., Miller, Michael B., Zhou, Zinan, Bohrson, Craig L., Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A., Garaycoechea, Juan I., Gawad, Charles, West, Jay, Walsh, Christopher A., and Park, Peter J.

Published
2022
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9. Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias

Author

D’Gama, Alissa M, Woodworth, Mollie B, Hossain, Amer A, Bizzotto, Sara, Hatem, Nicole E, LaCoursiere, Christopher M, Najm, Imad, Ying, Zhong, Yang, Edward, Barkovich, A James, Kwiatkowski, David J, Vinters, Harry V, Madsen, Joseph R, Mathern, Gary W, Blümcke, Ingmar, Poduri, Annapurna, and Walsh, Christopher A

Subjects
Brain Disorders, Epilepsy, Human Genome, Stem Cell Research - Nonembryonic - Non-Human, Neurodegenerative, Stem Cell Research, Congenital Structural Anomalies, Cancer, Genetics, Rare Diseases, Neurosciences, Pediatric, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Cell Lineage, Class I Phosphatidylinositol 3-Kinases, Hemimegalencephaly, High-Throughput Nucleotide Sequencing, Humans, Malformations of Cortical Development, Mice, Mutation, Neurons, Signal Transduction, Stem Cells, TOR Serine-Threonine Kinases, Telencephalon, brain malformations, cortical development, epilepsy, excitatory neurons, focal cortical dysplasia, hemimegalancephaly, mTOR pathway, next-generation sequencing, single-cell sequencing, somatic mutations, Biochemistry and Cell Biology, Medical Physiology
Abstract

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

Published
2017

10. Single-cell genotyping and transcriptomic profiling in focal cortical dysplasia

Author

Baulac, Stephanie, primary, Baldassari, Sara, additional, Klingler, Esther, additional, Teijeiro, Lucia Gomez, additional, Doladilhe, Marion, additional, Raoux, Corentin, additional, Roig-Puiggros, Sergi, additional, Bizzotto, Sara, additional, Sami, Lina, additional, Ribierre, Theo, additional, Aronica, Eleonora, additional, Adle-Biassette, Homa, additional, Chipaux, Mathilde, additional, and Jabaudon, Denis, additional

Published
2024
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12. Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex

Author

Kim, Sonia Nan, primary, Viswanadham, Vinayak V., additional, Doan, Ryan N., additional, Dou, Yanmei, additional, Bizzotto, Sara, additional, Khoshkhoo, Sattar, additional, Huang, August Yue, additional, Yeh, Rebecca, additional, Chhouk, Brian, additional, Truong, Alex, additional, Chappell, Kathleen M., additional, Beaudin, Marc, additional, Barton, Alison, additional, Akula, Shyam K., additional, Rento, Lariza, additional, Lodato, Michael, additional, Ganz, Javier, additional, Szeto, Ryan A., additional, Li, Pengpeng, additional, Tsai, Jessica W., additional, Hill, Robert Sean, additional, Park, Peter J., additional, and Walsh, Christopher A., additional

Published
2023
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13. Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

Author

Maury, Eduardo A., primary, Sherman, Maxwell A., additional, Genovese, Giulio, additional, Gilgenast, Thomas G., additional, Kamath, Tushar, additional, Burris, S.J., additional, Rajarajan, Prashanth, additional, Flaherty, Erin, additional, Akbarian, Schahram, additional, Chess, Andrew, additional, McCarroll, Steven A., additional, Loh, Po-Ru, additional, Phillips-Cremins, Jennifer E., additional, Brennand, Kristen J., additional, Macosko, Evan Z., additional, Walters, James T.R., additional, O’Donovan, Michael, additional, Sullivan, Patrick, additional, Sebat, Jonathan, additional, Lee, Eunjung A., additional, Walsh, Christopher A., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Thiruvahindrapuram, Bhooma, additional, Wang, Zhouzhi, additional, Scherer, Stephen W., additional, Howrigan, Daniel P, additional, Ripke, Stephan, additional, Bulik-Sullivan, Brendan, additional, Farh, Kai-How, additional, Fromer, Menachem, additional, Goldstein, Jacqueline I., additional, Huang, Hailiang, additional, Lee, Phil, additional, Daly, Mark J., additional, Neale, Benjamin M., additional, Belliveau, Richard A., additional, Bergen, Sarah E., additional, Bevilacqua, Elizabeth, additional, Chambert, Kimberley D., additional, O'Dushlaine, Colm, additional, Scolnick, Edward M., additional, Smoller, Jordan W., additional, Moran, Jennifer L., additional, Palotie, Aarno, additional, Petryshen, Tracey L., additional, Wu, Wenting, additional, Greer, Douglas S., additional, Antaki, Danny, additional, Shetty, Aniket, additional, Gujral, Madhusudan, additional, Brandler, William M., additional, Malhotra, Dheeraj, additional, Fuentes Fajarado, Karin V., additional, Maile, Michelle S., additional, Holmans, Peter A., additional, Carrera, Noa, additional, Craddock, Nick, additional, Escott-Price, Valentina, additional, Georgieva, Lyudmila, additional, Hamshere, Marian L., additional, Kavanagh, David, additional, Legge, Sophie E., additional, Pocklington, Andrew J., additional, Richards, Alexander L., additional, Ruderfer, Douglas M., additional, Williams, Nigel M., additional, Kirov, George, additional, Owen, Michael J., additional, Pinto, Dalila, additional, Cai, Guiqing, additional, Davis, Kenneth L., additional, Drapeau, Elodie, additional, Friedman, Joseph I, additional, Haroutunian, Vahram, additional, Parkhomenko, Elena, additional, Reichenberg, Abraham, additional, Silverman, Jeremy M., additional, Buxbaum, Joseph D., additional, Domenici, Enrico, additional, Agartz, Ingrid, additional, Djurovic, Srdjan, additional, Mattingsdal, Morten, additional, Melle, Ingrid, additional, Andreassen, Ole A., additional, Jönsson, Erik G., additional, Söderman, Erik, additional, Albus, Margot, additional, Alexander, Madeline, additional, Laurent, Claudine, additional, Levinson, Douglas F., additional, Amin, Farooq, additional, Atkins, Joshua, additional, Cairns, Murray J., additional, Scott, Rodney J., additional, Tooney, Paul A., additional, Wu, Jing Qin, additional, Bacanu, Silviu A., additional, Bigdeli, Tim B., additional, Reimers, Mark A., additional, Webb, Bradley T., additional, Wolen, Aaron R., additional, Wormley, Brandon K., additional, Kendler, Kenneth S., additional, Riley, Brien P., additional, Kähler, Anna K., additional, Magnusson, Patrik K.E., additional, Hultman, Christina M., additional, Bertalan, Marcelo, additional, Hansen, Thomas, additional, Olsen, Line, additional, Rasmussen, Henrik B., additional, Werge, Thomas, additional, Mattheisen, Manuel, additional, Black, Donald W., additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buckner, Randy L., additional, Roffman, Joshua L., additional, Byerley, William, additional, Cahn, Wiepke, additional, Kahn, René S, additional, Strengman, Eric, additional, Ophoff, Roel A., additional, Carr, Vaughan J., additional, Catts, Stanley V., additional, Henskens, Frans A., additional, Loughland, Carmel M., additional, Michie, Patricia T., additional, Pantelis, Christos, additional, Schall, Ulrich, additional, Jablensky, Assen V., additional, Kelly, Brian J., additional, Campion, Dominique, additional, Cantor, Rita M., additional, Cheng, Wei, additional, Cloninger, C. Robert, additional, Svrakic, Dragan M, additional, Cohen, David, additional, Cormican, Paul, additional, Donohoe, Gary, additional, Morris, Derek W., additional, Corvin, Aiden, additional, Gill, Michael, additional, Crespo-Facorro, Benedicto, additional, Crowley, James J., additional, Farrell, Martilias S., additional, Giusti-Rodríguez, Paola, additional, Kim, Yunjung, additional, Szatkiewicz, Jin P., additional, Williams, Stephanie, additional, Curtis, David, additional, Pimm, Jonathan, additional, Gurling, Hugh, additional, McQuillin, Andrew, additional, Davidson, Michael, additional, Weiser, Mark, additional, Degenhardt, Franziska, additional, Forstner, Andreas J., additional, Herms, Stefan, additional, Hoffmann, Per, additional, Hofman, Andrea, additional, Cichon, Sven, additional, Nöthen, Markus M., additional, Del Favero, Jurgen, additional, DeLisi, Lynn E., additional, McCarley, Robert W., additional, Levy, Deborah L., additional, Mesholam-Gately, Raquelle I., additional, Seidman, Larry J., additional, Dikeos, Dimitris, additional, Papadimitriou, George N., additional, Dinan, Timothy, additional, Duan, Jubao, additional, Sanders, Alan R., additional, Gejman, Pablo V., additional, Gershon, Elliot S., additional, Dudbridge, Frank, additional, Eichhammer, Peter, additional, Eriksson, Johan, additional, Salomaa, Veikko, additional, Essioux, Laurent, additional, Fanous, Ayman H., additional, Knowles, James A., additional, Pato, Michele T., additional, Pato, Carlos N., additional, Frank, Josef, additional, Meier, Sandra, additional, Schulze, Thomas G., additional, Strohmaier, Jana, additional, Witt, Stephanie H., additional, Rietschel, Marcella, additional, Franke, Lude, additional, Karjalainen, Juha, additional, Freedman, Robert, additional, Olincy, Ann, additional, Freimer, Nelson B., additional, Purcell, Shaun M., additional, Roussos, Panos, additional, Stahl, Eli A., additional, Sklar, Pamela, additional, Giegling, Ina, additional, Hartmann, Annette M., additional, Konte, Bettina, additional, Rujescu, Dan, additional, Godard, Stephanie, additional, Hirschhorn, Joel N., additional, Pers, Tune H., additional, Price, Alkes, additional, Esko, Tõnu, additional, Gratten, Jacob, additional, Lee, S. Hong, additional, Visscher, Peter M., additional, Wray, Naomi R., additional, Mowry, Bryan J., additional, de Haan, Lieuwe, additional, Meijer, Carin J., additional, Hansen, Mark, additional, Ikeda, Masashi, additional, Iwata, Nakao, additional, Joa, Inge, additional, Kalaydjieva, Luba, additional, Keller, Matthew C., additional, Kennedy, James L., additional, Zai, Clement C., additional, Knight, Jo, additional, Lerer, Bernard, additional, Liang, Kung-Yee, additional, Lieberman, Jeffrey, additional, Stroup, T. Scott, additional, Lönnqvist, Jouko, additional, Suvisaari, Jaana, additional, Maher, Brion S., additional, Maier, Wolfgang, additional, Mallet, Jacques, additional, McDonald, Colm, additional, McIntosh, Andrew M., additional, Blackwood, Douglas H.R., additional, Metspalu, Andres, additional, Milani, Lili, additional, Milanova, Vihra, additional, Mokrab, Younes, additional, Collier, David A., additional, Müller-Myhsok, Bertram, additional, Murphy, Kieran C., additional, Murray, Robin M., additional, Powell, John, additional, Myin-Germeys, Inez, additional, Van Os, Jim, additional, Nenadic, Igor, additional, Nertney, Deborah A., additional, Nestadt, Gerald, additional, Pulver, Ann E., additional, Nicodemus, Kristin K., additional, Nisenbaum, Laura, additional, Nordin, Annelie, additional, Adolfsson, Rolf, additional, O'Callaghan, Eadbhard, additional, Oh, Sang-Yun, additional, O'Neill, F. Anthony, additional, Paunio, Tiina, additional, Pietiläinen, Olli, additional, Perkins, Diana O., additional, Quested, Digby, additional, Savitz, Adam, additional, Li, Qingqin S., additional, Schwab, Sibylle G., additional, Shi, Jianxin, additional, Spencer, Chris C.A., additional, Thirumalai, Srinivas, additional, Veijola, Juha, additional, Waddington, John, additional, Walsh, Dermot, additional, Wildenauer, Dieter B., additional, Bramon, Elvira, additional, Darvasi, Ariel, additional, Posthuma, Danielle, additional, St. Clair, David, additional, Shanta, Omar, additional, Klein, Marieke, additional, Park, Peter J., additional, Weinberger, Daniel, additional, Moran, John V., additional, Gage, Fred H., additional, Vaccarino, Flora M., additional, Gleeson, Joseph, additional, Mathern, Gary, additional, Courchesne, Eric, additional, Roy, Subhojit, additional, Bizzotto, Sara, additional, Coulter, Michael, additional, Dias, Caroline, additional, D'Gama, Alissa, additional, Ganz, Javier, additional, Hill, Robert, additional, Huang, August Yue, additional, Khoshkhoo, Sattar, additional, Kim, Sonia, additional, Lodato, Michael, additional, Miller, Michael, additional, Borges-Monroy, Rebeca, additional, Rodin, Rachel, additional, Zhou, Zinan, additional, Bohrson, Craig, additional, Chu, Chong, additional, Cortes-Ciriano, Isidro, additional, Dou, Yanmei, additional, Galor, Alon, additional, Gulhan, Doga, additional, Kwon, Minseok, additional, Luquette, Joe, additional, Viswanadham, Vinay, additional, Jones, Attila, additional, Rosenbluh, Chaggai, additional, Cho, Sean, additional, Langmead, Ben, additional, Thorpe, Jeremy, additional, Erwin, Jennifer, additional, Jaffe, Andrew, additional, McConnell, Michael, additional, Narurkar, Rujuta, additional, Paquola, Apua, additional, Shin, Jooheon, additional, Straub, Richard, additional, Abyzov, Alexej, additional, Bae, Taejeong, additional, Jang, Yeongjun, additional, Wang, Yifan, additional, Gage, Fred, additional, Linker, Sara, additional, Reed, Patrick, additional, Wang, Meiyan, additional, Urban, Alexander, additional, Zhou, Bo, additional, Zhu, Xiaowei, additional, Pattni, Reenal, additional, Amero, Aitor Serres, additional, Juan, David, additional, Lobon, Irene, additional, Marques-Bonet, Tomas, additional, Moruno, Manuel Solis, additional, Perez, Raquel Garcia, additional, Povolotskaya, Inna, additional, Soriano, Eduardo, additional, Averbuj, Dan, additional, Ball, Laurel, additional, Breuss, Martin, additional, Yang, Xiaoxu, additional, Chung, Changuk, additional, Emery, Sarah B., additional, Flasch, Diane A., additional, Kidd, Jeffrey M., additional, Kopera, Huira C., additional, Kwan, Kenneth Y., additional, Mills, Ryan E., additional, Moldovan, John B., additional, Sun, Chen, additional, Zhao, Xuefang, additional, Zhou, Weichen, additional, Frisbie, Trenton J., additional, Cherskov, Adriana, additional, Fasching, Liana, additional, Jourdon, Alexandre, additional, Pochareddy, Sirisha, additional, Scuderi, Soraya, additional, and Sestan, Nenad, additional

Published
2023
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14. Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Author

Khoshkhoo, Sattar, primary, Wang, Yilan, additional, Chahine, Yasmine, additional, Erson-Omay, E. Zeynep, additional, Robert, Stephanie M., additional, Kiziltug, Emre, additional, Damisah, Eyiyemisi C., additional, Nelson-Williams, Carol, additional, Zhu, Guangya, additional, Kong, Wenna, additional, Huang, August Yue, additional, Stronge, Edward, additional, Phillips, H. Westley, additional, Chhouk, Brian H., additional, Bizzotto, Sara, additional, Chen, Ming Hui, additional, Adikari, Thiuni N., additional, Ye, Zimeng, additional, Witkowski, Tom, additional, Lai, Dulcie, additional, Lee, Nadine, additional, Lokan, Julie, additional, Scheffer, Ingrid E., additional, Berkovic, Samuel F., additional, Haider, Shozeb, additional, Hildebrand, Michael S., additional, Yang, Edward, additional, Gunel, Murat, additional, Lifton, Richard P., additional, Richardson, R. Mark, additional, Blümcke, Ingmar, additional, Alexandrescu, Sanda, additional, Huttner, Anita, additional, Heinzen, Erin L., additional, Zhu, Jidong, additional, Poduri, Annapurna, additional, DeLanerolle, Nihal, additional, Spencer, Dennis D., additional, Lee, Eunjung Alice, additional, Walsh, Christopher A., additional, and Kahle, Kristopher T., additional

Published
2023
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20. Somatic Ras/Raf/MAPK Variants Enriched in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Author

Khoshkhoo, Sattar, primary, Wang, Yilan, additional, Chahine, Yasmine, additional, Erson-Omay, E. Zeynep, additional, Robert, Stephanie, additional, Kiziltug, Emre, additional, Damisah, Eyiyemisi C., additional, Nelson-Williams, Carol, additional, Zhu, Guangya, additional, Kong, Wenna, additional, Huang, August Yue, additional, Stronge, Edward, additional, Phillips, H. Westley, additional, Chhouk, Brian H., additional, Bizzotto, Sara, additional, Chen, Ming Hui, additional, Adikari, Thiuni N., additional, Ye, Zimeng, additional, Witkowski, Tom, additional, Lai, Dulcie, additional, Lee, Nadine, additional, Lokan, Julie, additional, Scheffer, Ingrid E., additional, Berkovic, Samuel F., additional, Haider, Shozeb, additional, Hildebrand, Michael S., additional, Yang, Edward, additional, Gunel, Murat, additional, Lifton, Richard P., additional, Richardson, R Mark, additional, Blümcke, Ingmar, additional, Alexandrescu, Sanda, additional, Huttner, Anita, additional, Heinzen, Erin L., additional, Zhu, Jidong, additional, Poduri, Annapurna, additional, DeLanerolle, Nihal, additional, Spencer, Dennis D., additional, Lee, Eunjung Alice, additional, Walsh, Christopher A., additional, and Kahle, Kristopher T., additional

Published
2022
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21. Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements

Author

Luquette, Lovelace J, Miller, Michael B, Zhou, Zinan, Bohrson, Craig L, Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A, Garaycoechea, Juan I, Gawad, Charles, West, Jay, Walsh, Christopher A, Park, Peter J, Luquette, Lovelace J, Miller, Michael B, Zhou, Zinan, Bohrson, Craig L, Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A, Garaycoechea, Juan I, Gawad, Charles, West, Jay, Walsh, Christopher A, and Park, Peter J

Abstract

Accurate somatic mutation detection from single-cell DNA sequencing is challenging due to amplification-related artifacts. To reduce this artifact burden, an improved amplification technique, primary template-directed amplification (PTA), was recently introduced. We analyzed whole-genome sequencing data from 52 PTA-amplified single neurons using SCAN2, a new genotyper we developed to leverage mutation signatures and allele balance in identifying somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) in PTA data. Our analysis confirms an increase in nonclonal somatic mutation in single neurons with age, but revises the estimated rate of this accumulation to 16 SNVs per year. We also identify artifacts in other amplification methods. Most importantly, we show that somatic indels increase by at least three per year per neuron and are enriched in functional regions of the genome such as enhancers and promoters. Our data suggest that indels in gene-regulatory elements have a considerable effect on genome integrity in human neurons.

Published
2022

22. Single-cell genome sequencing of human neurons identifies somatic point mutation and indel enrichment in regulatory elements

Author

Hubrecht Institute with UMC, Luquette, Lovelace J., Miller, Michael B., Zhou, Zinan, Bohrson, Craig L., Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A., Garaycoechea, Juan I., Gawad, Charles, West, Jay, Walsh, Christopher A., Park, Peter J., Hubrecht Institute with UMC, Luquette, Lovelace J., Miller, Michael B., Zhou, Zinan, Bohrson, Craig L., Zhao, Yifan, Jin, Hu, Gulhan, Doga, Ganz, Javier, Bizzotto, Sara, Kirkham, Samantha, Hochepied, Tino, Libert, Claude, Galor, Alon, Kim, Junho, Lodato, Michael A., Garaycoechea, Juan I., Gawad, Charles, West, Jay, Walsh, Christopher A., and Park, Peter J.

Published
2022

23. Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain

Author

Ganz, Javier, primary, Maury, Eduardo A., additional, Becerra, Basheer, additional, Bizzotto, Sara, additional, Doan, Ryan N., additional, Kenny, Connor J., additional, Shin, Taehwan, additional, Kim, Junho, additional, Zhou, Zinan, additional, Ligon, Keith L., additional, Lee, Eunjung Alice, additional, and Walsh, Christopher A., additional

Published
2021
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24. Additional file 1 of Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Yifan Wang, Taejeong Bae, Thorpe, Jeremy, Sherman, Maxwell A., Jones, Attila G., Cho, Sean, Daily, Kenneth, Yanmei Dou, Ganz, Javier, Galor, Alon, Lobon, Irene, Reenal Pattni, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Xiaoxu Yang, Zhou, Bo, Schahram Akbarian, Ball, Laurel L., Bizzotto, Sara, Emery, Sarah B., Doan, Ryan, Fasching, Liana, Yeongjun Jang, Juan, David, Lizano, Esther, Lovelace J. Luquette, Moldovan, John B., Rujuta Narurkar, Oetjens, Matthew T., Rodin, Rachel E., Shobana Sekar, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E., Weichen Zhou, Chess, Andrew, Gleeson, Joseph G., Marquès-Bonet, Tomas, Park, Peter J., Peters, Mette A., Pevsner, Jonathan, Walsh, Christopher A., Weinberger, Daniel R., Vaccarino, Flora M., Moran, John V., Urban, Alexander E., Kidd, Jeffrey M., Mills, Ryan E., and Abyzov, Alexej

Abstract

Additional file 1:. Figure S1-S13, Table S1,S3,S4.

Published
2021
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25. Additional file 5 of Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Yifan Wang, Taejeong Bae, Thorpe, Jeremy, Sherman, Maxwell A., Jones, Attila G., Cho, Sean, Daily, Kenneth, Yanmei Dou, Ganz, Javier, Galor, Alon, Lobon, Irene, Reenal Pattni, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Xiaoxu Yang, Zhou, Bo, Schahram Akbarian, Ball, Laurel L., Bizzotto, Sara, Emery, Sarah B., Doan, Ryan, Fasching, Liana, Yeongjun Jang, Juan, David, Lizano, Esther, Lovelace J. Luquette, Moldovan, John B., Rujuta Narurkar, Oetjens, Matthew T., Rodin, Rachel E., Shobana Sekar, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E., Weichen Zhou, Chess, Andrew, Gleeson, Joseph G., Marquès-Bonet, Tomas, Park, Peter J., Peters, Mette A., Pevsner, Jonathan, Walsh, Christopher A., Weinberger, Daniel R., Vaccarino, Flora M., Moran, John V., Urban, Alexander E., Kidd, Jeffrey M., Mills, Ryan E., and Abyzov, Alexej

Abstract

Additional file 5. BSMN_Membership_List.

Published
2021
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26. Additional file 6 of Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Yifan Wang, Taejeong Bae, Thorpe, Jeremy, Sherman, Maxwell A., Jones, Attila G., Cho, Sean, Daily, Kenneth, Yanmei Dou, Ganz, Javier, Galor, Alon, Lobon, Irene, Reenal Pattni, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Xiaoxu Yang, Zhou, Bo, Schahram Akbarian, Ball, Laurel L., Bizzotto, Sara, Emery, Sarah B., Doan, Ryan, Fasching, Liana, Yeongjun Jang, Juan, David, Lizano, Esther, Lovelace J. Luquette, Moldovan, John B., Rujuta Narurkar, Oetjens, Matthew T., Rodin, Rachel E., Shobana Sekar, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E., Weichen Zhou, Chess, Andrew, Gleeson, Joseph G., Marquès-Bonet, Tomas, Park, Peter J., Peters, Mette A., Pevsner, Jonathan, Walsh, Christopher A., Weinberger, Daniel R., Vaccarino, Flora M., Moran, John V., Urban, Alexander E., Kidd, Jeffrey M., Mills, Ryan E., and Abyzov, Alexej

Abstract

Additional file 6. Review history.

Published
2021
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28. Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A, Jones, Attila G, Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L, Bizzotto, Sara, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A, Jones, Attila G, Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobon, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L, and Bizzotto, Sara

Abstract

Background Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells. Results Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees. Conclusions This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

Published
2021

29. Comprehensive identification of somatic nucleotide variants in human brain tissue

Author

National Institute of Mental Health (US), Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A., Jones, Attila G., Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobón, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L., Bizzotto, Sara, Emery, Sarah B., Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J., Moldovan, John B., Narurkar, Rujuta, Oetjens, Matthew T., Rodin, Rachel E., Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E., Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G., Marqués-Bonet, Tomàs, Park, Peter J., Peters, Mette A., Pevsner, Jonathan, Walsh, Christopher A., Weinberger, Daniel R., Brain Somatic Mosaicism Network, Vaccarino, Flora M., Moran, John V., Urban, Alexander E., Kidd, Jeffrey M., Mills, Ryan E., Abyzov, Alexej, National Institute of Mental Health (US), Wang, Yifan, Bae, Taejeong, Thorpe, Jeremy, Sherman, Maxwell A., Jones, Attila G., Cho, Sean, Daily, Kenneth, Dou, Yanmei, Ganz, Javier, Galor, Alon, Lobón, Irene, Pattni, Reenal, Rosenbluh, Chaggai, Tomasi, Simone, Tomasini, Livia, Yang, Xiaoxu, Zhou, Bo, Akbarian, Schahram, Ball, Laurel L., Bizzotto, Sara, Emery, Sarah B., Doan, Ryan, Fasching, Liana, Jang, Yeongjun, Juan, David, Lizano, Esther, Luquette, Lovelace J., Moldovan, John B., Narurkar, Rujuta, Oetjens, Matthew T., Rodin, Rachel E., Sekar, Shobana, Shin, Joo Heon, Soriano, Eduardo, Straub, Richard E., Zhou, Weichen, Chess, Andrew, Gleeson, Joseph G., Marqués-Bonet, Tomàs, Park, Peter J., Peters, Mette A., Pevsner, Jonathan, Walsh, Christopher A., Weinberger, Daniel R., Brain Somatic Mosaicism Network, Vaccarino, Flora M., Moran, John V., Urban, Alexander E., Kidd, Jeffrey M., Mills, Ryan E., and Abyzov, Alexej

Abstract

[Background] Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells., [Results] Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees., [Conclusions] This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases.

Published
2021

30. Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Author

Pathologie, Pathologie Pathologen staf, Cancer, Blümcke, Ingmar, Coras, Roland, Busch, Robyn M, Morita-Sherman, Marcia, Lal, Dennis, Prayson, Richard, Cendes, Fernando, Lopes-Cendes, Iscia, Rogerio, Fabio, Almeida, Vanessa S, Rocha, Cristiane S, Sim, Nam Suk, Lee, Jeong Ho, Kim, Se Hoon, Baulac, Stephanie, Baldassari, Sara, Adle-Biassette, Homa, Walsh, Christopher A, Bizzotto, Sara, Doan, Ryan N, Morillo, Katherine S, Aronica, Eleonora, Mühlebner, Angelika, Becker, Albert, Cienfuegos, Jesus, Garbelli, Rita, Giannini, Caterina, Honavar, Mrinalini, Jacques, Thomas S, Thom, Maria, Mahadevan, Anita, Miyata, Hajime, Niehusmann, Pitt, Sarnat, Harvey B, Söylemezoglu, Figen, Najm, Imad, Pathologie, Pathologie Pathologen staf, Cancer, Blümcke, Ingmar, Coras, Roland, Busch, Robyn M, Morita-Sherman, Marcia, Lal, Dennis, Prayson, Richard, Cendes, Fernando, Lopes-Cendes, Iscia, Rogerio, Fabio, Almeida, Vanessa S, Rocha, Cristiane S, Sim, Nam Suk, Lee, Jeong Ho, Kim, Se Hoon, Baulac, Stephanie, Baldassari, Sara, Adle-Biassette, Homa, Walsh, Christopher A, Bizzotto, Sara, Doan, Ryan N, Morillo, Katherine S, Aronica, Eleonora, Mühlebner, Angelika, Becker, Albert, Cienfuegos, Jesus, Garbelli, Rita, Giannini, Caterina, Honavar, Mrinalini, Jacques, Thomas S, Thom, Maria, Mahadevan, Anita, Miyata, Hajime, Niehusmann, Pitt, Sarnat, Harvey B, Söylemezoglu, Figen, and Najm, Imad

Published
2021

31. Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial

Author

Blümcke, Ingmar, primary, Coras, Roland, additional, Busch, Robyn M., additional, Morita‐Sherman, Marcia, additional, Lal, Dennis, additional, Prayson, Richard, additional, Cendes, Fernando, additional, Lopes‐Cendes, Iscia, additional, Rogerio, Fabio, additional, Almeida, Vanessa S., additional, Rocha, Cristiane S., additional, Sim, Nam Suk, additional, Lee, Jeong Ho, additional, Kim, Se Hoon, additional, Baulac, Stephanie, additional, Baldassari, Sara, additional, Adle‐Biassette, Homa, additional, Walsh, Christopher A., additional, Bizzotto, Sara, additional, Doan, Ryan N., additional, Morillo, Katherine S., additional, Aronica, Eleonora, additional, Mühlebner, Angelika, additional, Becker, Albert, additional, Cienfuegos, Jesus, additional, Garbelli, Rita, additional, Giannini, Caterina, additional, Honavar, Mrinalini, additional, Jacques, Thomas S., additional, Thom, Maria, additional, Mahadevan, Anita, additional, Miyata, Hajime, additional, Niehusmann, Pitt, additional, Sarnat, Harvey B., additional, Söylemezoglu, Figen, additional, and Najm, Imad, additional

Published
2021
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32. Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex

Author

Bizzotto, Sara, Uzquiano, Ana, Dingli, Florent, Ershov, Dmitry, Houllier, Anne, Arras, Guillaume, Richards, Mark, Loew, Damarys, Minc, Nicolas, Croquelois, Alexandre, Houdusse, Anne, Francis, Fiona, Francis, Fiona, Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Boston Children's Hospital, Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Leicester, Université de Lausanne = University of Lausanne (UNIL), Biologie Cellulaire et Cancer, and Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cerebral Cortex, Mice, Knockout, [SDV]Life Sciences [q-bio], lcsh:R, lcsh:Medicine, Classical Lissencephalies and Subcortical Band Heterotopias, Spindle Apparatus, Article, [SDV] Life Sciences [q-bio], Mice, Neural Stem Cells, Animals, Female, lcsh:Q, lcsh:Science, Microtubule-Associated Proteins, Cells, Cultured, Cerebral Cortex/metabolism, Cerebral Cortex/pathology, Classical Lissencephalies and Subcortical Band Heterotopias/metabolism, Classical Lissencephalies and Subcortical Band Heterotopias/pathology, Microtubule-Associated Proteins/physiology, Neural Stem Cells/metabolism, Neural Stem Cells/pathology, Spindle Apparatus/metabolism, Spindle Apparatus/pathology
Abstract

International audience; The ventricular zone (VZ) of the developing cerebral cortex is a pseudostratified epithelium that contains progenitors undergoing precisely regulated divisions at its most apical side, the ventricular lining (VL). Mitotic perturbations can contribute to pathological mechanisms leading to cortical malformations. The HeCo mutant mouse exhibits subcortical band heterotopia (SBH), likely to be initiated by progenitor delamination from the VZ early during corticogenesis. The causes for this are however, currently unknown. Eml1, a microtubule (MT)-associated protein of the EMAP family, is impaired in these mice. We first show that MT dynamics are perturbed in mutant progenitor cells in vitro. These may influence interphase and mitotic MT mechanisms and indeed, centrosome and primary cilia were altered and spindles were found to be abnormally long in HeCo progenitors. Consistently, MT and spindle length regulators were identified in EML1 pulldowns from embryonic brain extracts. Finally, we found that mitotic cell shape is also abnormal in the mutant VZ. These previously unidentified VZ characteristics suggest altered cell constraints which may contribute to cell delamination.

Published
2017

36. Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias.

Author

D'Gama, Alissa M, D'Gama, Alissa M, Woodworth, Mollie B, Hossain, Amer A, Bizzotto, Sara, Hatem, Nicole E, LaCoursiere, Christopher M, Najm, Imad, Ying, Zhong, Yang, Edward, Barkovich, A James, Kwiatkowski, David J, Vinters, Harry V, Madsen, Joseph R, Mathern, Gary W, Blümcke, Ingmar, Poduri, Annapurna, Walsh, Christopher A, D'Gama, Alissa M, D'Gama, Alissa M, Woodworth, Mollie B, Hossain, Amer A, Bizzotto, Sara, Hatem, Nicole E, LaCoursiere, Christopher M, Najm, Imad, Ying, Zhong, Yang, Edward, Barkovich, A James, Kwiatkowski, David J, Vinters, Harry V, Madsen, Joseph R, Mathern, Gary W, Blümcke, Ingmar, Poduri, Annapurna, and Walsh, Christopher A

Abstract

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia.

Published
2017

37. Morphological and functional aspects of progenitors perturbed in cortical malformations

Author

Bizzotto, Sara, Francis, Fiona, Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and HAL-UPMC, Gestionnaire

Subjects
neurodevelopment, intellectual disability, proliferation, radial glial cells, lamination, epilepsy, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Review Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], mouse mutant, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Neuroscience, lcsh:RC321-571
Abstract

International audience; In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area.

Published
2015

38. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human

Author

Agence Nationale de la Recherche (France), Fondation Bettencourt Schueller, Fédération pour la Recherche sur le Cerveau (France), Swiss National Science Foundation, European Commission, Fondation pour la Recherche Médicale, Ministerio de Economía y Competitividad (España), Kielar, Michel, Phan Dinh Tuy, Françoise, Bizzotto, Sara, Lebrand, Cécile, Juan Romero, Camino de, Poirier, Karine, Oegema, Renske, Mancini, Grazia Maria, Bahi-Buisson, Nadia, Olaso, Robert, Le Moing, Anne-Gaëlle, Boutourlinsky, Katia, Boucher, Dominique, Carpentier, Wassila, Berquin, Patrick, Deleuze, Jean-François, Belvindrah, Richard, Borrell, Víctor, Welker, Egbert, Chelly, Jamel, Croquelois, Alexandre, Francis, Fiona, Agence Nationale de la Recherche (France), Fondation Bettencourt Schueller, Fédération pour la Recherche sur le Cerveau (France), Swiss National Science Foundation, European Commission, Fondation pour la Recherche Médicale, Ministerio de Economía y Competitividad (España), Kielar, Michel, Phan Dinh Tuy, Françoise, Bizzotto, Sara, Lebrand, Cécile, Juan Romero, Camino de, Poirier, Karine, Oegema, Renske, Mancini, Grazia Maria, Bahi-Buisson, Nadia, Olaso, Robert, Le Moing, Anne-Gaëlle, Boutourlinsky, Katia, Boucher, Dominique, Carpentier, Wassila, Berquin, Patrick, Deleuze, Jean-François, Belvindrah, Richard, Borrell, Víctor, Welker, Egbert, Chelly, Jamel, Croquelois, Alexandre, and Francis, Fiona

Abstract

Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Eml1 knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.

Published
2014

40. Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human

Author

Kielar, Michel, primary, Tuy, Françoise Phan Dinh, additional, Bizzotto, Sara, additional, Lebrand, Cécile, additional, de Juan Romero, Camino, additional, Poirier, Karine, additional, Oegema, Renske, additional, Mancini, Grazia Maria, additional, Bahi-Buisson, Nadia, additional, Olaso, Robert, additional, Le Moing, Anne-Gaëlle, additional, Boutourlinsky, Katia, additional, Boucher, Dominique, additional, Carpentier, Wassila, additional, Berquin, Patrick, additional, Deleuze, Jean-François, additional, Belvindrah, Richard, additional, Borrell, Victor, additional, Welker, Egbert, additional, Chelly, Jamel, additional, Croquelois, Alexandre, additional, and Francis, Fiona, additional

Published
2014
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42. Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex.

Author

Kim SN, Viswanadham VV, Doan RN, Dou Y, Bizzotto S, Khoshkhoo S, Huang AY, Yeh R, Chhouk B, Truong A, Chappell KM, Beaudin M, Barton A, Akula SK, Rento L, Lodato M, Ganz J, Szeto RA, Li P, Tsai JW, Hill RS, Park PJ, and Walsh CA

Abstract

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages., Competing Interests: Declaration of Interests The authors declare no competing interests.

Published
2023
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43. Contrasting patterns of somatic mutations in neurons and glia reveal differential predisposition to disease in the aging human brain.

Author

Ganz J, Luquette LJ, Bizzotto S, Bohrson CL, Jin H, Miller MB, Zhou Z, Galor A, Park PJ, and Walsh CA

Abstract

Characterizing the mechanisms of somatic mutations in the brain is important for understanding aging and disease, but little is known about the mutational patterns of different cell types. We performed whole-genome sequencing of 71 oligodendrocytes and 51 neurons from neurotypical individuals (0.4 to 104 years old) and identified >67,000 somatic single nucleotide variants (sSNVs) and small insertions and deletions (indels). While both cell types accumulate mutations with age, oligodendrocytes accumulate sSNVs 69% faster than neurons (27/year versus 16/year) whereas indels accumulate 42% slower (1.8/year versus 3.1/year). Correlation with single-cell RNA and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These patterns highlight differences in the mutagenic processes in glia and neurons and suggest cell type-specific, age-related contributions to neurodegeneration and oncogenesis.

Published
2023
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44. Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain.

Author

Ganz J, Maury EA, Becerra B, Bizzotto S, Doan RN, Kenny CJ, Shin T, Kim J, Zhou Z, Ligon KL, Lee EA, and Walsh CA

Subjects
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Child, Child, Preschool, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Oncogenes, Polymorphism, Single Nucleotide, Young Adult, Brain pathology, Brain Neoplasms genetics
Abstract

Although oncogenic mutations have been found in nondiseased, proliferative nonneural tissues, their prevalence in the human brain is unknown. Targeted sequencing of genes implicated in brain tumors in 418 samples derived from 110 individuals of varying ages, without tumor diagnoses, detected oncogenic somatic single-nucleotide variants (sSNV) in 5.4% of the brains, including IDH1 R132H . These mutations were largely present in subcortical white matter and enriched in glial cells and, surprisingly, were less common in older individuals. A depletion of high-allele frequency sSNVs representing macroscopic clones with age was replicated by analysis of bulk RNA sequencing data from 1,816 nondiseased brain samples ranging from fetal to old age. We also describe large clonal copy number variants and that sSNVs show mutational signatures resembling those found in gliomas, suggesting that mutational processes of the normal brain drive early glial oncogenesis. This study helps understand the origin and early evolution of brain tumors. SIGNIFICANCE: In the nondiseased brain, clonal oncogenic mutations are enriched in white matter and are less common in older individuals. We revealed early steps in acquiring oncogenic variants, which are essential to understanding brain tumor origins and building new mutational baselines for diagnostics. This article is highlighted in the In This Issue feature, p. 1 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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45. Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias.

Author

D'Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM, Najm I, Ying Z, Yang E, Barkovich AJ, Kwiatkowski DJ, Vinters HV, Madsen JR, Mathern GW, Blümcke I, Poduri A, and Walsh CA

Subjects
Animals, Cell Lineage, Class I Phosphatidylinositol 3-Kinases genetics, Hemimegalencephaly genetics, Hemimegalencephaly pathology, High-Throughput Nucleotide Sequencing, Humans, Mice, Neurons metabolism, Neurons pathology, Malformations of Cortical Development genetics, Mutation genetics, Signal Transduction, Stem Cells metabolism, TOR Serine-Threonine Kinases metabolism, Telencephalon pathology
Abstract

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 of 66 cases (41%). Radiographically indistinguishable lesions are caused by somatic activating mutations in AKT3, MTOR, and PIK3CA and germline loss-of-function mutations in DEPDC5, NPRL2, and TSC1/2, including TSC2 mutations in isolated HME demonstrating a "two-hit" model. Mutations in the same gene cause a disease continuum from FCD to HME to bilateral brain overgrowth, reflecting the progenitor cell and developmental time when the mutation occurred. Single-cell sequencing demonstrated mTOR activation in neurons in all lesions. Conditional Pik3ca activation in the mouse cortex showed that mTOR activation in excitatory neurons and glia, but not interneurons, is sufficient for abnormal cortical overgrowth. These data suggest that mTOR activation in dorsal telencephalic progenitors, in some cases specifically the excitatory neuron lineage, causes cortical dysplasia., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2017
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46. Morphological and functional aspects of progenitors perturbed in cortical malformations.

Author

Bizzotto S and Francis F

Abstract

In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area.

Published
2015
Full Text
View/download PDF

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