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23 results on '"Gage, Fred H."'

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

2. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons

Author

Reid, Dylan A, Reed, Patrick J, Schlachetzki, Johannes CM, Nitulescu, Ioana I, Chou, Grace, Tsui, Enoch C, Jones, Jeffrey R, Chandran, Sahaana, Lu, Ake T, McClain, Claire A, Ooi, Jean H, Wang, Tzu-Wen, Lana, Addison J, Linker, Sara B, Ricciardulli, Anthony S, Lau, Shong, Schafer, Simon T, Horvath, Steve, Dixon, Jesse R, Hah, Nasun, Glass, Christopher K, and Gage, Fred H

Subjects
Stem Cell Research, Neurosciences, Regenerative Medicine, Aging, Genetics, Human Genome, Underpinning research, 1.1 Normal biological development and functioning, DNA Damage, DNA Repair, DNA, Intergenic, Deoxyuridine, Embryonic Stem Cells, Genome, Human, Genomic Instability, Histones, Humans, Mitosis, Mutation, Nervous System Diseases, Neurons, Promoter Regions, Genetic, RNA-Binding Proteins, Sequence Analysis, DNA, Transcription, Genetic, General Science & Technology
Abstract

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

Published
2021

3. Brain cell type–specific enhancer–promoter interactome maps and disease-risk association

Author

Nott, Alexi, Holtman, Inge R, Coufal, Nicole G, Schlachetzki, Johannes CM, Yu, Miao, Hu, Rong, Han, Claudia Z, Pena, Monique, Xiao, Jiayang, Wu, Yin, Keulen, Zahara, Pasillas, Martina P, O'Connor, Carolyn, Nickl, Christian K, Schafer, Simon T, Shen, Zeyang, Rissman, Robert A, Brewer, James B, Gosselin, David, Gonda, David D, Levy, Michael L, Rosenfeld, Michael G, McVicker, Graham, Gage, Fred H, Ren, Bing, and Glass, Christopher K

Subjects
Biological Sciences, Genetics, Brain Disorders, Dementia, Alzheimer's Disease, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Human Genome, Stem Cell Research, Acquired Cognitive Impairment, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Brain, Cells, Cultured, Chromatin, Enhancer Elements, Genetic, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Humans, Microglia, Nuclear Proteins, Promoter Regions, Genetic, Sequence Deletion, Tumor Suppressor Proteins, General Science & Technology
Abstract

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.

Published
2019

4. High-resolution comparative analysis of great ape genomes

Author

Kronenberg, Zev N, Fiddes, Ian T, Gordon, David, Murali, Shwetha, Cantsilieris, Stuart, Meyerson, Olivia S, Underwood, Jason G, Nelson, Bradley J, Chaisson, Mark JP, Dougherty, Max L, Munson, Katherine M, Hastie, Alex R, Diekhans, Mark, Hormozdiari, Fereydoun, Lorusso, Nicola, Hoekzema, Kendra, Qiu, Ruolan, Clark, Karen, Raja, Archana, Welch, AnneMarie E, Sorensen, Melanie, Baker, Carl, Fulton, Robert S, Armstrong, Joel, Graves-Lindsay, Tina A, Denli, Ahmet M, Hoppe, Emma R, Hsieh, PingHsun, Hill, Christopher M, Pang, Andy Wing Chun, Lee, Joyce, Lam, Ernest T, Dutcher, Susan K, Gage, Fred H, Warren, Wesley C, Shendure, Jay, Haussler, David, Schneider, Valerie A, Cao, Han, Ventura, Mario, Wilson, Richard K, Paten, Benedict, Pollen, Alex, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Stem Cell Research, Human Genome, Biotechnology, Aetiology, Underpinning research, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Animals, Contig Mapping, Evolution, Molecular, Genetic Variation, Genome, Human, Hominidae, Humans, Molecular Sequence Annotation, Sequence Analysis, DNA, General Science & Technology
Abstract

Genetic studies of human evolution require high-quality contiguous ape genome assemblies that are not guided by the human reference. We coupled long-read sequence assembly and full-length complementary DNA sequencing with a multiplatform scaffolding approach to produce ab initio chimpanzee and orangutan genome assemblies. By comparing these with two long-read de novo human genome assemblies and a gorilla genome assembly, we characterized lineage-specific and shared great ape genetic variation ranging from single- to mega-base pair-sized variants. We identified ~17,000 fixed human-specific structural variants identifying genic and putative regulatory changes that have emerged in humans since divergence from nonhuman apes. Interestingly, these variants are enriched near genes that are down-regulated in human compared to chimpanzee cerebral organoids, particularly in cells analogous to radial glial neural progenitors.

Published
2018

5. An environment-dependent transcriptional network specifies human microglia identity

Author

Gosselin, David, Skola, Dylan, Coufal, Nicole G, Holtman, Inge R, Schlachetzki, Johannes CM, Sajti, Eniko, Jaeger, Baptiste N, O'Connor, Carolyn, Fitzpatrick, Conor, Pasillas, Martina P, Pena, Monique, Adair, Amy, Gonda, David D, Levy, Michael L, Ransohoff, Richard M, Gage, Fred H, and Glass, Christopher K

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurosciences, Brain Disorders, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Animals, Brain Neoplasms, Cells, Cultured, Environment, Epilepsy, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Humans, Male, Mice, Mice, Inbred C57BL, Microglia, General Science & Technology
Abstract

Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.

Published
2017

9. Intersection of diverse neuronal genomes and neuropsychiatric disease : The Brain Somatic Mosaicism Network

Author

Brain Somatic Mosaicism Network, McConnell, Michael J., Moran, John V., Abyzov, Alexej, Akbarian, Schahram, Bae, Taejeong, Cortes-Ciriano, Isidro, Erwin, Jennifer A., Fasching, Liana, Flasch, Diane A., Freed, Donald, Ganz, Javier, Jaffe, Andrew E., Kwan, Kenneth Y., Kwon, Minseok, Lodato, Michael A., Mills, Ryan E., Paquola, Apua C. M., Rodin, Rachel E., Rosenbluh, Chaggai, Sestan, Nenad, Sherman, Maxwell A., Shin, Joo Heon, Song, Saera, Straub, Richard E., Thorpe, Jeremy, Weinberger, Daniel R., Urban, Alexander E., Zhou, Bo, Gage, Fred H., Lehner, Thomas, Senthil, Geetha, A. Walsh, Christopher, Chess, Andrew, Courchesne, Eric, Gleeson, Joseph G., Kidd, Jeffrey M., Park, Peter J., Pevsner, Jonathan, and Vaccarino, Flora M.

Published
2017

16. Mosaic Copy Number Variation in Human Neurons

Author

McConnell, Michael J., Lindberg, Michael R., Brennend, Kristen J., Piper, Julia C., Voet, Thierry, Cowing-Zitron, Chris, Shumilina, Svetlana, Lasken, Roger S., Vermeesch, Joris R., Hall, Ira M., and Gage, Fred H.

Published
2013
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