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1. Areal specializations in the morpho-electric and transcriptomic properties of primate layer 5 extratelencephalic projection neurons

Author

Nikolai C. Dembrow, Scott Sawchuk, Rachel Dalley, Ximena Opitz-Araya, Mark Hudson, Cristina Radaelli, Lauren Alfiler, Sarah Walling-Bell, Darren Bertagnolli, Jeff Goldy, Nelson Johansen, Jeremy A. Miller, Kamiliam Nasirova, Scott F. Owen, Alejandro Parga-Becerra, Naz Taskin, Michael Tieu, David Vumbaco, Natalie Weed, Julia Wilson, Brian R. Lee, Kimberly A. Smith, Staci A. Sorensen, William J. Spain, Ed S. Lein, Steve I. Perlmutter, Jonathan T. Ting, and Brian E. Kalmbach

Subjects
CP: Neuroscience, Biology (General), QH301-705.5
Abstract

Summary: Large-scale analysis of single-cell gene expression has revealed transcriptomically defined cell subclasses present throughout the primate neocortex with gene expression profiles that differ depending upon neocortical region. Here, we test whether the interareal differences in gene expression translate to regional specializations in the physiology and morphology of infragranular glutamatergic neurons by performing Patch-seq experiments in brain slices from the temporal cortex (TCx) and motor cortex (MCx) of the macaque. We confirm that transcriptomically defined extratelencephalically projecting neurons of layer 5 (L5 ET neurons) include retrogradely labeled corticospinal neurons in the MCx and find multiple physiological properties and ion channel genes that distinguish L5 ET from non-ET neurons in both areas. Additionally, while infragranular ET and non-ET neurons retain distinct neuronal properties across multiple regions, there are regional morpho-electric and gene expression specializations in the L5 ET subclass, providing mechanistic insights into the specialized functional architecture of the primate neocortex.

Published
2024
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2. INTER-INDIVIDUAL VARIATION IN HUMAN CORTICAL CELL TYPE ABUNDANCE AND EXPRESSION

Author

Nelson Johansen, Saroja Somasundaram, Kyle Travaglini, Anna Marie Yanny, Maya Shumyatcher, Tamara Casper, Charles Cobbs, Nick Dee, Richard Ellenbogen, Manuel Ferreira, Jeff Goldy, Junitta Guzman, Ryder Gwinn, Daniel Hirschstein, Nikolas Jorstad, C. Dirk Keene, Andrew Ko, Boaz Levi, Jeffrey Ojemann, Thanh Pham, Nadiya Shapovalova, Daniel Silbergeld, Josef Sulc, Amy Torkelson, Herman Tung, Kimberly Smith, Ed Lein, Trygve Bakken, Rebecca Hodge, and Jeremy Miller

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Published
2023
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3. Single-cell and single-nucleus RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates, and humans

Author

Trygve E Bakken, Cindy TJ van Velthoven, Vilas Menon, Rebecca D Hodge, Zizhen Yao, Thuc Nghi Nguyen, Lucas T Graybuck, Gregory D Horwitz, Darren Bertagnolli, Jeff Goldy, Anna Marie Yanny, Emma Garren, Sheana Parry, Tamara Casper, Soraya I Shehata, Eliza R Barkan, Aaron Szafer, Boaz P Levi, Nick Dee, Kimberly A Smith, Susan M Sunkin, Amy Bernard, John Phillips, Michael J Hawrylycz, Christof Koch, Gabe J Murphy, Ed Lein, Hongkui Zeng, and Bosiljka Tasic

Subjects
maccaca nemestrina, macaca fascicularis, single-cell RNA-seq, species comparison, lateral geniculate nucleus, Medicine, Science, Biology (General), QH301-705.5
Abstract

Abundant evidence supports the presence of at least three distinct types of thalamocortical (TC) neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex (V1). Different types of TC neurons in mice, humans, and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of TC neurons in the primate dLGN: magnocellular (M) neurons, parvocellular (P) neurons, and two types of koniocellular (K) neurons. Despite extensively documented morphological and physiological differences between M and P neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. Likewise, the dominant feature of TC neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to the observed differences in morphology and cortical projection targets. Finally, alignment of transcriptome profiles across species highlights expanded diversity of GABAergic neurons in primate versus mouse dLGN and homologous types of TC neurons in primates that are distinct from TC neurons in mouse.

Published
2021
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4. Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

Author

Adam K. Savage, Miriam V. Gutschow, Tony Chiang, Kathy Henderson, Richard Green, Monica Chaudhari, Elliott Swanson, Alexander T. Heubeck, Nina Kondza, Kelli C. Burley, Palak C. Genge, Cara Lord, Tanja Smith, Zachary Thomson, Aldan Beaubien, Ed Johnson, Jeff Goldy, Hamid Bolouri, Jane H. Buckner, Paul Meijer, Ernest M. Coffey, Peter J. Skene, Troy R. Torgerson, Xiao-jun Li, and Thomas F. Bumol

Subjects
Molecular Physiology, Immunology, Proteomics, Transcriptomics, Science
Abstract

Summary: Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states.

Published
2021
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5. Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex

Author

John K. Mich, Lucas T. Graybuck, Erik E. Hess, Joseph T. Mahoney, Yoshiko Kojima, Yi Ding, Saroja Somasundaram, Jeremy A. Miller, Brian E. Kalmbach, Cristina Radaelli, Bryan B. Gore, Natalie Weed, Victoria Omstead, Yemeserach Bishaw, Nadiya V. Shapovalova, Refugio A. Martinez, Olivia Fong, Shenqin Yao, Marty Mortrud, Peter Chong, Luke Loftus, Darren Bertagnolli, Jeff Goldy, Tamara Casper, Nick Dee, Ximena Opitz-Araya, Ali Cetin, Kimberly A. Smith, Ryder P. Gwinn, Charles Cobbs, Andrew L. Ko, Jeffrey G. Ojemann, C. Dirk Keene, Daniel L. Silbergeld, Susan M. Sunkin, Viviana Gradinaru, Gregory D. Horwitz, Hongkui Zeng, Bosiljka Tasic, Ed S. Lein, Jonathan T. Ting, and Boaz P. Levi

Subjects
human, macaque, brain cell types, epigenetics, enhancers, AAVs, Biology (General), QH301-705.5
Abstract

Summary: Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection of Parvalbumin (PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primate neocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools.

Published
2021
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6. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types.

Author

Trygve E Bakken, Rebecca D Hodge, Jeremy A Miller, Zizhen Yao, Thuc Nghi Nguyen, Brian Aevermann, Eliza Barkan, Darren Bertagnolli, Tamara Casper, Nick Dee, Emma Garren, Jeff Goldy, Lucas T Graybuck, Matthew Kroll, Roger S Lasken, Kanan Lathia, Sheana Parry, Christine Rimorin, Richard H Scheuermann, Nicholas J Schork, Soraya I Shehata, Michael Tieu, John W Phillips, Amy Bernard, Kimberly A Smith, Hongkui Zeng, Ed S Lein, and Bosiljka Tasic

Subjects
Medicine, Science
Abstract

Transcriptomic profiling of complex tissues by single-nucleus RNA-sequencing (snRNA-seq) affords some advantages over single-cell RNA-sequencing (scRNA-seq). snRNA-seq provides less biased cellular coverage, does not appear to suffer cell isolation-based transcriptional artifacts, and can be applied to archived frozen specimens. We used well-matched snRNA-seq and scRNA-seq datasets from mouse visual cortex to compare cell type detection. Although more transcripts are detected in individual whole cells (~11,000 genes) than nuclei (~7,000 genes), we demonstrate that closely related neuronal cell types can be similarly discriminated with both methods if intronic sequences are included in snRNA-seq analysis. We estimate that the nuclear proportion of total cellular mRNA varies from 20% to over 50% for large and small pyramidal neurons, respectively. Together, these results illustrate the high information content of nuclear RNA for characterization of cellular diversity in brain tissues.

Published
2018
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7. Neuropathological and transcriptomic characteristics of the aged brain

Author

Jeremy A Miller, Angela Guillozet-Bongaarts, Laura E Gibbons, Nadia Postupna, Anne Renz, Allison E Beller, Susan M Sunkin, Lydia Ng, Shannon E Rose, Kimberly A Smith, Aaron Szafer, Chris Barber, Darren Bertagnolli, Kristopher Bickley, Krissy Brouner, Shiella Caldejon, Mike Chapin, Mindy L Chua, Natalie M Coleman, Eiron Cudaback, Christine Cuhaciyan, Rachel A Dalley, Nick Dee, Tsega Desta, Tim A Dolbeare, Nadezhda I Dotson, Michael Fisher, Nathalie Gaudreault, Garrett Gee, Terri L Gilbert, Jeff Goldy, Fiona Griffin, Caroline Habel, Zeb Haradon, Nika Hejazinia, Leanne L Hellstern, Steve Horvath, Kim Howard, Robert Howard, Justin Johal, Nikolas L Jorstad, Samuel R Josephsen, Chihchau L Kuan, Florence Lai, Eric Lee, Felix Lee, Tracy Lemon, Xianwu Li, Desiree A Marshall, Jose Melchor, Shubhabrata Mukherjee, Julie Nyhus, Julie Pendergraft, Lydia Potekhina, Elizabeth Y Rha, Samantha Rice, David Rosen, Abharika Sapru, Aimee Schantz, Elaine Shen, Emily Sherfield, Shu Shi, Andy J Sodt, Nivretta Thatra, Michael Tieu, Angela M Wilson, Thomas J Montine, Eric B Larson, Amy Bernard, Paul K Crane, Richard G Ellenbogen, C Dirk Keene, and Ed Lein

Subjects
Alzheimer's disease, aging, dementia, gene expression, Medicine, Science, Biology (General), QH301-705.5
Abstract

As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer’s disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

Published
2017
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8. A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain

Author

Zizhen Yao, Cindy T. J. van Velthoven, Michael Kunst, Meng Zhang, Delissa McMillen, Changkyu Lee, Won Jung, Jeff Goldy, Aliya Abdelhak, Pamela Baker, Eliza Barkan, Darren Bertagnolli, Jazmin Campos, Daniel Carey, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Sakshi Chavan, Min Chen, Michael Clark, Jennie Close, Kirsten Crichton, Scott Daniel, Tim Dolbeare, Lauren Ellingwood, James Gee, Alexandra Glandon, Jessica Gloe, Joshua Gould, James Gray, Nathan Guilford, Junitta Guzman, Daniel Hirschstein, Windy Ho, Kelly Jin, Matthew Kroll, Kanan Lathia, Arielle Leon, Brian Long, Zoe Maltzer, Naomi Martin, Rachel McCue, Emma Meyerdierks, Thuc Nghi Nguyen, Trangthanh Pham, Christine Rimorin, Augustin Ruiz, Nadiya Shapovalova, Cliff Slaughterbeck, Josef Sulc, Michael Tieu, Amy Torkelson, Herman Tung, Nasmil Valera Cuevas, Katherine Wadhwani, Katelyn Ward, Boaz Levi, Colin Farrell, Carol L. Thompson, Shoaib Mufti, Chelsea M. Pagan, Lauren Kruse, Nick Dee, Susan M. Sunkin, Luke Esposito, Michael J. Hawrylycz, Jack Waters, Lydia Ng, Kimberly A. Smith, Bosiljka Tasic, Xiaowei Zhuang, and Hongkui Zeng

Subjects
Article
Abstract

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single- cell RNA-sequencing (scRNA-seq) dataset of ∼7 million cells profiled, and a spatially resolved transcriptomic dataset of ∼4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

Published
2023

9. Human neocortical expansion involves glutamatergic neuron diversification

Author

Tim S. Heistek, Thomas Braun, Natalia A. Goriounova, Michael Tieu, Lindsay Ng, Michael Hawrylycz, Kris Bickley, Anton Arkhipov, Colin Farrell, Trangthanh Pham, Alexandra Glandon, Daniel Park, Gábor Molnár, Herman Tung, Allan R. Jones, Lisa Keene, Gáspár Oláh, Thomas Chartrand, Amy Torkelson, Jae Geun Yoon, Rachel A. Dalley, Aaron Szafer, Nick Dee, Brian E. Kalmbach, Eliza Barkan, Allison Beller, Krissy Brouner, Andrew L. Ko, Alex M. Henry, Viktor Szemenyei, Julie Nyhus, Staci A. Sorensen, Samuel Dingman Lee, Norbert Mihut, Amy Bernard, Lisa Kim, Anatoly Buchin, Melissa Gorham, Lucas T. Graybuck, Lydia Potekhina, Katelyn Ward, Caitlin S. Latimer, Aaron Oldre, Gabe J. Murphy, Boaz P. Levi, Trygve E. Bakken, René Wilbers, Jonathan T. Ting, Kimberly A. Smith, Amanda Gary, Songlin Ding, Alice Mukora, Matthew Kroll, Anoop P. Patel, Wayne Wakeman, Hongkui Zeng, Nadezhda Dotson, Rusty Mann, Victoria Omstead, Leona Mezei, Desiree A. Marshall, Shea Ransford, Lydia Ng, Sara Kebede, Gábor Tamás, Jeffrey G. Ojemann, Stephanie Mok, Nathan Hansen, Christina A. Pom, Brian Lee, Jim Berg, Ramkumar Rajanbabu, John W. Phillips, Philip R. Nicovich, Matthew Mallory, Richard G. Ellenbogen, Rachel Enstrom, Luke Esposito, Tim Jarsky, Di Jon Hill, Idan Segev, Darren Bertagnolli, Agata Budzillo, Sander Idema, Daniel L. Silbergeld, Costas A. Anastassiou, Chris Hill, Michelle Maxwell, Mean Hwan Kim, Charles Cobbs, Delissa McMillen, Bosiljka Tasic, Olivia Fong, Medea McGraw, Hong Gu, Kirsten Crichton, David Reid, Kristen Hadley, Lauren Alfiler, Manuel Ferreira, Elliot R. Thomsen, Kiet Ngo, Josef Sulc, Augustin Ruiz, Katherine Baker, Zizhen Yao, Erica J. Melief, Femke Waleboer, Hanchuan Peng, Grace Williams, Rebecca D. Hodge, Kyla Berry, Katherine E. Link, David Sandman, Tsega Desta, Christine Rimorin, Jeff Goldy, Ryder P. Gwinn, Djai B. Heyer, Changkyu Lee, Jeremy A. Miller, Nathan W. Gouwens, Pál Barzó, Attila Ozsvár, Huibert D. Mansvelder, Sergey L. Gratiy, Rafael Yuste, David Feng, Jessica Trinh, Clare Gamlin, Tamara Casper, C. Dirk Keene, Susan M. Sunkin, Tom Egdorf, Philip C. De Witt Hamer, Rebecca de Frates, Peter Chong, Szabina Furdan, Patrick R. Hof, Jasmine Bomben, Christiaan P. J. de Kock, Eline J. Mertens, Ed S. Lein, Anna A. Galakhova, Florence D’Orazi, Christof Koch, Madie Hupp, Neurosurgery, Amsterdam Neuroscience - Systems & Network Neuroscience, Integrative Neurophysiology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention

Subjects
Cell type, Multidisciplinary, Neocortex, Neurofilament, Molecular neuroscience, Biology, Article, Cellular neuroscience, chemistry.chemical_compound, Glutamatergic, medicine.anatomical_structure, chemistry, Biocytin, medicine, Neuron, Neuroscience
Abstract

The neocortex is disproportionately expanded in human compared with mouse1,2, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth3. Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer’s disease4,5. Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., Combined patch clamp recording, biocytin staining and single-cell RNA-sequencing of human neurocortical neurons shows an expansion of glutamatergic neuron types relative to mouse that characterizes the greater complexity of the human neocortex.

Published
2021

10. Local Connectivity and Synaptic Dynamics in Mouse and Human Neocortex

Author

Luke Campagnola, Stephanie C. Seeman, Thomas Chartrand, Lisa Kim, Alex Hoggarth, Clare Gamlin, Shinya Ito, Jessica Trinh, Pasha Davoudian, Cristina Radaelli, Mean-Hwan Kim, Travis Hage, Thomas Braun, Lauren Alfiler, Julia Andrade, Phillip Bohn, Rachel Dalley, Alex Henry, Sara Kebede, Mukora Alice, David Sandman, Grace Williams, Rachael Larsen, Corinne Teeter, Tanya L. Daigle, Kyla Berry, Nadia Dotson, Rachel Enstrom, Melissa Gorham, Madie Hupp, Samuel Dingman Lee, Kiet Ngo, Philip R. Nicovich, Lydia Potekhina, Shea Ransford, Amanda Gary, Jeff Goldy, Delissa McMillen, Trangthanh Pham, Michael Tieu, La’Akea Siverts, Miranda Walker, Colin Farrell, Martin Schroedter, Cliff Slaughterbeck, Charles Cobb, Richard Ellenbogen, Ryder P. Gwinn, C. Dirk Keene, Andrew L. Ko, Jeffrey G. Ojemann, Daniel L. Silbergeld, Daniel Carey, Tamara Casper, Kirsten Crichton, Michael Clark, Nick Dee, Lauren Ellingwood, Jessica Gloe, Matthew Kroll, Josef Sulc, Herman Tung, Katherine Wadhwani, Krissy Brouner, Tom Egdorf, Michelle Maxwell, Medea McGraw, Christina Alice Pom, Augustin Ruiz, Jasmine Bomben, David Feng, Nika Hejazinia, Shu Shi, Aaron Szafer, Wayne Wakeman, John Phillips, Amy Bernard, Luke Esposito, Florence D. D’Orazi, Susan Sunkin, Kimberly Smith, Bosiljka Tasic, Anton Arkhipov, Staci Sorensen, Ed Lein, Christof Koch, Gabe Murphy, Hongkui Zeng, and Tim Jarsky

Subjects
Adult, Male, Neurons, Multidisciplinary, Models, Neurological, Datasets as Topic, Excitatory Postsynaptic Potentials, Mice, Transgenic, Neocortex, Synaptic Transmission, Article, Temporal Lobe, Mice, Inhibitory Postsynaptic Potentials, Neural Pathways, Synapses, Animals, Humans, Female, Visual Cortex
Abstract

We present a unique, extensive, and open synaptic physiology analysis platform and dataset. Through its application, we reveal principles that relate cell type to synaptic properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Synaptic properties are heterogeneous in most subclass-to-subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, whereas the strength axis accounts for substantial heterogeneity within the subclass. In the human cortex, excitatory-to-excitatory synaptic dynamics are distinct from those in the mouse cortex and vary with depth across layers 2 and 3.

Published
2022

11. Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Owen White, Kimberly A. Smith, Brian D. Aevermann, William J. Romanow, Joseph R. Ecker, Michael Tieu, Michael Hawrylycz, Sheng-Yong Niu, Brian R. Herb, Jacinta Lucero, Sten Linnarsson, Tanya L. Daigle, Christine S. Liu, Ed S. Lein, Boudewijn P. F. Lelieveldt, Zizhen Yao, Yang Eric Li, Stephan Fischer, Trygve E. Bakken, Jeremy A. Miller, C. Dirk Keene, Scott F. Owen, Wei Tian, Joshua Orvis, Nongluk Plongthongkum, Rosa Castanon, Megan Crow, Thomas Höllt, Bing Ren, Darren Bertagnolli, Weixiu Dong, Herman Tung, Baldur van Lew, Delissa McMillen, Bosiljka Tasic, Angeline Rivkin, Eran A. Mukamel, Nora Reed, Alexander Dobin, Chongyuan Luo, Patrick R. Hof, Nick Dee, Rongxin Fang, Kirsten Crichton, M. Margarita Behrens, Anna Bartlett, Renee Zhang, Olivier Poirion, Josef Sulc, Philip R. Nicovich, Rebecca D. Hodge, Evan Z. Macosko, Staci A. Sorensen, Dinh Diep, Thanh Pham, Songlin Ding, Richard H. Scheuermann, Jayaram Kancherla, Jeroen Eggermont, Seth A. Ament, Ronna Hertzano, Jeff Goldy, Christine Rimorin, Julia K. Osteen, Kimberly Siletti, Steven A. McCarroll, Hanqing Liu, C. Palmer, Saroja Somasundaram, Jonathan T. Ting, Jerold Chun, Xiaomeng Hou, Guoping Feng, Kun Zhang, Fenna M. Krienen, Blue B. Lake, Amy Torkelson, Hongkui Zeng, Sebastian Preissl, Christof Koch, Nikolas L. Jorstad, Andrew L. Ko, Héctor Corrada Bravo, Aviv Regev, Nikolai C. Dembrow, Kanan Lathia, Antonio Pinto-Duarte, Xinxin Wang, Lucas T. Graybuck, Melissa Goldman, Marmar Moussa, William J. Spain, Peter V. Kharchenko, Qiwen Hu, Adriana E. Sedeno-Cortes, Gregory D. Horwitz, Rachel A. Dalley, Anup Mahurkar, Brian E. Kalmbach, Andrew Aldridge, Jesse Gillis, Anna Marie Yanny, Joseph R. Nery, Tamara Casper, Fangming Xie, and Matthew Kroll

Subjects
Epigenomics, Male, Cell type, Genetics of the nervous system, Computational biology, Biology, Molecular neuroscience, Article, Epigenesis, Genetic, Transcriptome, Mice, Atlases as Topic, Glutamates, Species Specificity, Molecular evolution, Animals, Humans, GABAergic Neurons, Gene, In Situ Hybridization, Fluorescence, Phylogeny, Neurons, Multidisciplinary, Gene Expression Profiling, Motor Cortex, Callithrix, Epigenome, Middle Aged, Cellular neuroscience, Chromatin, Organ Specificity, DNA methylation, Female, Single-Cell Analysis
Abstract

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch–seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations., An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

Published
2021

12. Multimodal analysis for human ex vivo studies shows extensive molecular changes from delays in blood processing

Author

Kelli C. Burley, Hamid Bolouri, Jeff Goldy, Paul Meijer, Peter J Skene, Ed Johnson, Thomas F. Bumol, Tanja Smith, Elliott Swanson, Cara Lord, Miriam V. Gutschow, Aldan Beaubien, Alexander T. Heubeck, Zachary Thomson, Ernest M. Coffey, Adam K. Savage, Xiao-jun Li, Monica Chaudhari, Jane H. Buckner, Tony Chiang, Palak C Genge, Nina Kondza, Kathy Henderson, Richard Green, and Troy R. Torgerson

Subjects
0301 basic medicine, Proteomics, Cell type, Multidisciplinary, Science, Immunology, 02 engineering and technology, Biology, 021001 nanoscience & nanotechnology, Peripheral blood mononuclear cell, Phenotype, Article, Molecular Physiology, Transcriptome, 03 medical and health sciences, 030104 developmental biology, In vivo, Gene expression, Proteome, 0210 nano-technology, Transcriptomics, Ex vivo
Abstract

Summary Multi-omic profiling of human peripheral blood is increasingly utilized to identify biomarkers and pathophysiologic mechanisms of disease. The importance of these platforms in clinical and translational studies led us to investigate the impact of delayed blood processing on the numbers and state of peripheral blood mononuclear cells (PBMC) and on the plasma proteome. Similar to previous studies, we show minimal effects of delayed processing on the numbers and general phenotype of PBMC up to 18 hours. In contrast, profound changes in the single-cell transcriptome and composition of the plasma proteome become evident as early as 6 hours after blood draw. These reflect patterns of cellular activation across diverse cell types that lead to progressive distancing of the gene expression state and plasma proteome from native in vivo biology. Differences accumulating during an overnight rest (18 hours) could confound relevant biologic variance related to many underlying disease states., Graphical abstract, Highlights • Studies of human blood cells and plasma are highly sensitive to process variability • Time variability distorts biology in cutting-edge single-cell and multiplex assays • Longitudinal, multi-modal, and aligned data enable data qualification and exploration • Dataset holds potential novel, multi-modal biological correlations and hypotheses, Molecular Physiology ; Immunology ; Proteomics ; Transcriptomics

Published
2021

13. Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex

Author

Joseph T. Mahoney, Kimberly A. Smith, Refugio A. Martinez, Victoria Omstead, Ed S. Lein, Natalie Weed, Lucas T. Graybuck, Darren Bertagnolli, Luke Loftus, Jeffrey G. Ojemann, Boaz P. Levi, Jonathan T. Ting, John K. Mich, Yoshiko Kojima, Gregory D. Horwitz, Tamara Casper, Jeff Goldy, Andrew L. Ko, Yi Ding, Bryan B. Gore, Cristina Radaelli, C. Dirk Keene, Olivia Fong, Viviana Gradinaru, Marty Mortrud, Ximena Opitz-Araya, Yemeserach Bishaw, Nick Dee, Nadiya V. Shapovalova, Brian E. Kalmbach, Jeremy A. Miller, Hongkui Zeng, Charles Cobbs, Bosiljka Tasic, Daniel L. Silbergeld, Shenqin Yao, Ali Cetin, Ryder P. Gwinn, Hess Erik, Saroja Somasundaram, Peter Chong, and Susan M. Sunkin

Subjects
Primates, 0301 basic medicine, viruses, Genetic Vectors, Neocortex, ATAC-seq, Computational biology, Genome, Article, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, Mice, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, Databases, Genetic, Gene expression, medicine, Animals, Humans, Disease, Epigenetics, human, Enhancer, lcsh:QH301-705.5, Neurons, biology, epigenetics, macaque, Dependovirus, Chromatin, Enhancer Elements, Genetic, Parvalbumins, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, lcsh:Biology (General), AAVs, biology.protein, enhancers, 030217 neurology & neurosurgery, Parvalbumin, brain cell types
Abstract

SUMMARY Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-sub-class-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection of Parvalbumin (PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primate neocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools., Graphical Abstract, In brief Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Mich et al. use comparative open chromatin analysis to identify human neocortical enhancers that can drive gene expression from AAV vectors in a subclass-specific fashion in multiple species.

Published
2021

14. Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons

Author

Sergey L. Gratiy, Sara Kebede, Chris Hill, Clare Gamlin, Jeffrey G. Ojemann, Tom Egdorf, Ed S. Lein, Lydia Potekhina, Alice Mukora, Shea Ransford, Matthew Mallory, Tim S. Heistek, Jonathan T. Ting, Gábor Tamás, Philip C. De Witt Hamer, Rebecca de Frates, Medea McGraw, Gábor Molnár, Jim Berg, Szabina Furdan, Patrick R. Hof, Natalia A. Goriounova, David Feng, David Reid, Elliot R. Thomsen, Michael Tieu, Katelyn Ward, C. Dirk Keene, Florence D’Orazi, Mean Hwan Kim, Daniel Park, Amy Torkelson, Agata Budzillo, Katherine Baker, Michael Hawrylycz, Krissy Brouner, Andrew L. Ko, DiJon Hill, Kyla Berry, Peter Chong, Jessica Trinh, Desiree A. Marshall, Katherine E. Link, Brian Lee, Jasmine Bomben, Aaron Szafer, Gabe J. Murphy, Viktor Szemenyei, Madie Hupp, Lauren Alfiler, Nick Dee, Zizhen Yao, Luke Esposito, Tamara Casper, Erica J. Melief, Susan M. Sunkin, Lindsay Ng, Hongkui Zeng, Pál Barzó, Allison Beller, Lydia Ng, Charles Cobbs, Darren Bertagnolli, Kiet Ngo, Bosiljka Tasic, John W. Phillips, Christine Rimorin, Alex M. Henry, Aaron Oldre, Michelle Maxwell, Wayne Wakeman, Delissa McMillen, Amanda Gary, Tsega Desta, Nathan Hansen, Hong Gu, Julie Nyhus, Staci A. Sorensen, Gáspár Oláh, Thomas Chartrand, Kirsten Crichton, Matthew Kroll, Josef Sulc, Jeremy A. Miller, Amy Bernard, Lisa Kim, Herman Tung, Idan Segev, Kristen Hadley, David Sandman, Anoop P. Patel, Colin Farrell, Allan R. Jones, Lisa Keene, Sander Idema, Changkyu Lee, Stephanie Mok, Augustin Ruiz, Caitlin S. Latimer, Tim Jarsky, Kris Bickley, Anton Arkhipov, Ramkumar Rajanbabu, Thomas Braun, Costas A. Anastassiou, Anatoly Buchin, Nathan W. Gouwens, Philip R. Nicovich, Richard G. Ellenbogen, Olivia Fong, Grace Williams, Rachel Enstrom, Rachel A. Dalley, Daniel L. Silbergeld, Attila Ozsvár, Kimberly A. Smith, Ryder P. Gwinn, Songlin Ding, Rafael Yuste, Manuel Ferreira, Victoria Omstead, Samuel Dingman Lee, Norbert Mihut, Hanchuan Peng, Brian E. Kalmbach, Eliza Barkan, Melissa Gorham, Boaz P. Levi, Trygve E. Bakken, Jeff Goldy, Djai B. Heyer, Nadezhda Dotson, Rusty Mann, Rebecca D. Hodge, Christof Koch, René Wilbers, Leona Mezei, Eline J. Mertens, Jae-Geun Yoon, Anna A. Galakhova, Christina A. Pom, Trangthanh Pham, Alexandra Glandon, Christiaan P. J. de Kock, Lucas T. Graybuck, and Huibert D. Mansvelder

Subjects
0303 health sciences, Cell type, Neocortex, Neurofilament, Biology, Transcriptome, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, medicine.anatomical_structure, Cortex (anatomy), Specialization (functional), medicine, Neuroscience, 030217 neurology & neurosurgery, Function (biology), 030304 developmental biology
Abstract

The neocortex is disproportionately expanded in human compared to mouse, both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers that selectively make connections within the cortex and other telencephalic structures. Single-cell transcriptomic analyses of human and mouse cortex show an increased diversity of glutamatergic neuron types in supragranular cortex in human and pronounced gradients as a function of cortical depth. To probe the functional and anatomical correlates of this transcriptomic diversity, we describe a robust Patch-seq platform using neurosurgically-resected human tissues. We characterize the morphological and physiological properties of five transcriptomically defined human glutamatergic supragranular neuron types. Three of these types have properties that are specialized compared to the more homogeneous properties of transcriptomically defined homologous mouse neuron types. The two remaining supragranular neuron types, located exclusively in deep layer 3, do not have clear mouse homologues in supragranular cortex but are transcriptionally most similar to deep layer mouse intratelencephalic-projecting neuron types. Furthermore, we reveal the transcriptomic types in deep layer 3 that express high levels of non-phosphorylated heavy chain neurofilament protein that label long-range neurons known to be selectively depleted in Alzheimer’s disease. Together, these results demonstrate the power of transcriptomic cell type classification, provide a mechanistic underpinning for increased complexity of cortical function in human cortical evolution, and implicate discrete transcriptomic cell types as selectively vulnerable in disease.

Published
2020
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15. Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse

Author

Trygve E. Bakken, Nikolas L. Jorstad, Qiwen Hu, Blue B. Lake, Wei Tian, Brian E. Kalmbach, Megan Crow, Rebecca D. Hodge, Fenna M. Krienen, Staci A. Sorensen, Jeroen Eggermont, Zizhen Yao, Brian D. Aevermann, Andrew I. Aldridge, Anna Bartlett, Darren Bertagnolli, Tamara Casper, Rosa G. Castanon, Kirsten Crichton, Tanya L. Daigle, Rachel Dalley, Nick Dee, Nikolai Dembrow, Dinh Diep, Song-Lin Ding, Weixiu Dong, Rongxin Fang, Stephan Fischer, Melissa Goldman, Jeff Goldy, Lucas T. Graybuck, Brian R. Herb, Xiaomeng Hou, Jayaram Kancherla, Matthew Kroll, Kanan Lathia, Baldur van Lew, Yang Eric Li, Christine S. Liu, Hanqing Liu, Jacinta D. Lucero, Anup Mahurkar, Delissa McMillen, Jeremy A. Miller, Marmar Moussa, Joseph R. Nery, Philip R. Nicovich, Joshua Orvis, Julia K. Osteen, Scott Owen, Carter R. Palmer, Thanh Pham, Nongluk Plongthongkum, Olivier Poirion, Nora M. Reed, Christine Rimorin, Angeline Rivkin, William J. Romanow, Adriana E. Sedeño-Cortés, Kimberly Siletti, Saroja Somasundaram, Josef Sulc, Michael Tieu, Amy Torkelson, Herman Tung, Xinxin Wang, Fangming Xie, Anna Marie Yanny, Renee Zhang, Seth A. Ament, M. Margarita Behrens, Hector Corrada Bravo, Jerold Chun, Alexander Dobin, Jesse Gillis, Ronna Hertzano, Patrick R. Hof, Thomas Höllt, Gregory D. Horwitz, C. Dirk Keene, Peter V. Kharchenko, Andrew L. Ko, Boudewijn P. Lelieveldt, Chongyuan Luo, Eran A. Mukamel, Sebastian Preissl, Aviv Regev, Bing Ren, Richard H. Scheuermann, Kimberly Smith, William J. Spain, Owen R. White, Christof Koch, Michael Hawrylycz, Bosiljka Tasic, Evan Z. Macosko, Steven A. McCarroll, Jonathan T. Ting, Hongkui Zeng, Kun Zhang, Guoping Feng, Joseph R. Ecker, Sten Linnarsson, and Ed S. Lein

Subjects
Transcriptome, Cell type, biology, Evolutionary biology, biology.animal, DNA methylation, Marmoset, Epigenome, Gene, Chromatin, Epigenomics
Abstract

The primary motor cortex (M1) is essential for voluntary fine motor control and is functionally conserved across mammals. Using high-throughput transcriptomic and epigenomic profiling of over 450,000 single nuclei in human, marmoset monkey, and mouse, we demonstrate a broadly conserved cellular makeup of this region, whose similarity mirrors evolutionary distance and is consistent between the transcriptome and epigenome. The core conserved molecular identity of neuronal and non-neuronal types allowed the generation of a cross-species consensus cell type classification and inference of conserved cell type properties across species. Despite overall conservation, many species specializations were apparent, including differences in cell type proportions, gene expression, DNA methylation, and chromatin state. Few cell type marker genes were conserved across species, providing a short list of candidate genes and regulatory mechanisms responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allowed the Patch-seq identification of layer 5 (L5) corticospinal Betz cells in non-human primate and human and characterization of their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell type diversity in M1 across mammals and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Published
2020
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16. Toward an integrated classification of neuronal cell types: morphoelectric and transcriptomic characterization of individual GABAergic cortical neurons

Author

David Feng, Jessica Trinh, Tamara Casper, Lisa Kim, Rohan Gala, Clare Gamlin, Matthew Kroll, Uygar Sümbül, Lauren Alfiler, Thomas Braun, Jasmine Bomben, Bosiljka Tasic, Colin Farrell, Hongkui Zeng, Lydia Potekhina, Tsega Desta, Kiet Ngo, Lydia Ng, Alice Mukora, Fahimeh Baftizadeh, Aaron Szafer, Rachel A. Dalley, Shea Ransford, Changkyu Lee, Nick Dee, Brian Lee, Kirsten Crichton, Luke Esposito, Miranda Robertson, Josef Sulc, Alex M. Henry, Darren Bertagnolli, Tom Egdorf, Nadezhda Dotson, Zhi Zhou, Jim Berg, Philip R. Nicovich, Rusty Mann, Madie Hupp, Daniel Park, Delissa McMillen, Samuel Dingman Lee, Agata Budzillo, Eliza Barkan, Olivia Fong, Thanh Pham, Jeff Goldy, Ed S. Lein, Rebecca de Frates, Kimberly A. Smith, Amy Torkelson, Tim Jarsky, Michelle Maxwell, Michael Tieu, Susan M. Sunkin, Michael Hawrylycz, Lucas T. Graybuck, Herman Tung, David Reid, DiJon Hill, Alexandra Glandon, Kara Ronellenfitch, Aaron Oldre, Amanda Gary, Nathan W. Gouwens, Christof Koch, Alice Pom, Wayne Wakeman, Sara Kebede, Matthew Mallory, Tae Kyung Kim, Tanya L. Daigle, Kris Bickley, Anton Arkhipov, Osnat Penn, Staci A. Sorensen, Rachel Enstrom, Hanchuan Peng, Ramkumar Rajanbabu, Jonathan T. Ting, Zizhen Yao, Lauren Ellingwood, Medea McGraw, Gabe J. Murphy, Katherine Baker, Krissy Brouner, Hong Gu, David Sandman, Katelyn Ward, Kyla Berry, Katherine E. Link, Lindsay Ng, Christine Rimorin, Kristen Hadley, Augustin Ruiz, Grace Williams, and Melissa Gorham

Subjects
Transcriptome, Electrophysiology, Cell type, medicine.anatomical_structure, Visual cortex, Interneuron, nervous system, genetic structures, medicine, GABAergic, Cortical neurons, Biology, Neuroscience
Abstract

Neurons are frequently classified into distinct groups or cell types on the basis of structural, physiological, or genetic attributes. To better constrain the definition of neuronal cell types, we characterized the transcriptomes and intrinsic physiological properties of over 3,700 GABAergic mouse visual cortical neurons and reconstructed the local morphologies of 350 of those neurons. We found that most transcriptomic types (t-types) occupy specific laminar positions within mouse visual cortex, and many of those t-types exhibit consistent electrophysiological and morphological features. We observed that these properties could vary continuously between t-types, which limited the ability to predict specific t-types from other data modalities. Despite that, the data support the presence of at least 20 interneuron met-types that have congruent morphological, electrophysiological, and transcriptomic properties.HighlightsPatch-seq data obtained from >3,700 GABAergic cortical interneuronsComprehensive characterization of morpho-electric features of transcriptomic types20 interneuron met-types that have congruent properties across data modalitiesDifferent Sst met-types preferentially innervate different cortical layers

Published
2020
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17. Conserved cell types with divergent features in human versus mouse cortex

Author

Elliot R. Thomsen, Ahmed Mahfouz, Saroja Somasundaram, Aaron Oldre, Bosiljka Tasic, Songlin Ding, Richard H. Scheuermann, Daniel Hirschstein, Thomas Höllt, Christine Rimorin, Thuc Nghi Nguyen, Jennie L. Close, John W. Phillips, Lydia Ng, Jeff Goldy, Darren Bertagnolli, Amy Bernard, Zizhen Yao, Boaz P. Levi, Trygve E. Bakken, Soraya I. Shehata, Susan M. Sunkin, Osnat Penn, Michael Tieu, Allison Beller, Boudewijn P. F. Lelieveldt, Jeffrey G. Ojemann, Shannon Reynolds, Michael Hawrylycz, Jeroen Eggermont, Medea McGraw, Ryder P. Gwinn, Sheana Parry, Kimberly A. Smith, Brian Long, Olivia Fong, Zoe Maltzer, Rafael Yuste, David Feng, Julie Nyhus, Rebecca D. Hodge, Ed Lein, Jeremy A. Miller, Brian D. Aevermann, Gerald Quon, Emma Garren, Christof Koch, Aaron Szafer, Nick Dee, Nadiya V. Shapovalova, Rachel A. Dalley, Tamara Casper, Mohamed Keshk, Nelson Johansen, Krissy Brouner, Andrew L. Ko, Allan R. Jones, Eliza Barkan, Hongkui Zeng, Richard G. Ellenbogen, C. Dirk Keene, Kanan Lathia, Lucas T. Graybuck, and Charles Cobbs

Subjects
0301 basic medicine, Adult, Male, Cell type, Adolescent, General Science & Technology, Middle temporal gyrus, 1.1 Normal biological development and functioning, Biology, 03 medical and health sciences, Mice, Young Adult, 0302 clinical medicine, Single-cell analysis, Species Specificity, Underpinning research, Cortex (anatomy), medicine, Genetics, Animals, Humans, 2.1 Biological and endogenous factors, RNA-Seq, Aetiology, Aged, Cerebral Cortex, Neurons, Principal Component Analysis, Multidisciplinary, Cellular architecture, Neurosciences, Neural Inhibition, Human brain, Middle Aged, Biological Evolution, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Astrocytes, Neurological, Excitatory postsynaptic potential, Female, Single-Cell Analysis, Transcriptome, Neuroscience, 030217 neurology & neurosurgery
Abstract

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

Published
2019

18. Single-nucleus and single-cell transcriptomes compared in matched cortical cell types

Author

Jeremy A. Miller, Soraya I. Shehata, Thuc Nghi Nguyen, Matthew Kroll, Nick Dee, Sheana Parry, Rebecca D. Hodge, Kimberly A. Smith, Brian D. Aevermann, Ed Lein, Christine Rimorin, Darren Bertagnolli, Amy Bernard, Michael Tieu, Bosiljka Tasic, Eliza Barkan, Jeff Goldy, Emma Garren, Tamara Casper, Richard H. Scheuermann, Hongkui Zeng, Nicholas J. Schork, Trygve E. Bakken, Roger S. Lasken, Kanan Lathia, John W. Phillips, Lucas T. Graybuck, and Zizhen Yao

Subjects
0301 basic medicine, Cell, genetic processes, Gene Expression, Biochemistry, Transcriptome, Database and Informatics Methods, Mice, Single-cell analysis, Animal Cells, Gene expression, Visual Cortex, Neurons, Multidisciplinary, Mammalian Genomics, Messenger RNA, Genomics, Cell biology, Nucleic acids, medicine.anatomical_structure, Medicine, Cellular Types, Single-Cell Analysis, Transcriptome Analysis, Sequence Analysis, Research Article, Cell type, Sequence analysis, Bioinformatics, Science, Biology, Research and Analysis Methods, Genome Complexity, 03 medical and health sciences, medicine, Genetics, Animals, natural sciences, Cell Lineage, Molecular Biology Techniques, Molecular Biology, Cell Nucleus, Sequence Analysis, RNA, Gene Expression Profiling, Intron, Biology and Life Sciences, Computational Biology, Marker Genes, Cell Biology, Genome Analysis, Introns, 030104 developmental biology, Animal Genomics, Cellular Neuroscience, RNA, Nucleus, Sequence Alignment, Neuroscience
Abstract

Transcriptomic profiling of complex tissues by single-nucleus RNA-sequencing (snRNA-seq) affords some advantages over single-cell RNA-sequencing (scRNA-seq). snRNA-seq provides less biased cellular coverage, does not appear to suffer cell isolation-based transcriptional artifacts, and can be applied to archived frozen specimens. We used well-matched snRNA-seq and scRNA-seq datasets from mouse visual cortex to compare cell type detection. Although more transcripts are detected in individual whole cells (~11,000 genes) than nuclei (~7,000 genes), we demonstrate that closely related neuronal cell types can be similarly discriminated with both methods if intronic sequences are included in snRNA-seq analysis. We estimate that the nuclear proportion of total cellular mRNA varies from 20% to over 50% for large and small pyramidal neurons, respectively. Together, these results illustrate the high information content of nuclear RNA for characterization of cellular diversity in brain tissues.

Published
2018

19. Adult Mouse Cortical Cell Taxonomy by Single Cell Transcriptomics

Author

Linda Madisen, Kimberly A. Smith, Darren Bertagnolli, Amy Bernard, Tim Jarsky, Jeff Goldy, Tim A. Dolbeare, Hongkui Zeng, Lucas T. Gray, Christof Koch, Tae Kyung Kim, Susan M. Sunkin, Boaz P. Levi, Changkyu Lee, Bosiljka Tasic, Nadiya V. Shapovalova, Zizhen Yao, Michael Hawrylycz, Staci A. Sorensen, Thuc Nghi Nguyen, Sheana Parry, and Vilas Menon

Subjects
0301 basic medicine, Genetic Markers, Male, Cell type, Transgene, Cell, Glutamic Acid, Mice, Transgenic, Biology, Article, Cell Line, Transcriptome, 03 medical and health sciences, Mice, 0302 clinical medicine, Interneurons, medicine, Animals, Axon, gamma-Aminobutyric Acid, Gene Library, Visual Cortex, Neurons, Cerebral Cortex, Sequence Analysis, RNA, General Neuroscience, Classification, Molecular biology, Cell biology, Gene expression profiling, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Cell culture, RNA, Neuroscience, 030217 neurology & neurosurgery
Abstract

Nervous systems are composed of various cell types, but the extent of cell type diversity is poorly understood. We constructed a cellular taxonomy of one cortical region, primary visual cortex, in adult mice on the basis of single-cell RNA sequencing. We identified 49 transcriptomic cell types, including 23 GABAergic, 19 glutamatergic and 7 non-neuronal types. We also analyzed cell type-specific mRNA processing and characterized genetic access to these transcriptomic types by many transgenic Cre lines. Finally, we found that some of our transcriptomic cell types displayed specific and differential electrophysiological and axon projection properties, thereby confirming that the single-cell transcriptomic signatures can be associated with specific cellular properties.

Published
2016

20. Shared and distinct transcriptomic cell types across neocortical areas

Author

Daniel Hirschstein, Michael N. Economo, Allan R. Jones, Christine Rimorin, Eliza Barkan, Linda Madisen, Seana Parry, Susan M. Sunkin, Rachael Larsen, Hongkui Zeng, Tae Kyung Kim, Emma Garren, Kimberly A. Smith, Jeremy A. Miller, Osnat Penn, Olivia Fong, Sarada Viswanathan, Julie A. Harris, Bosiljka Tasic, Thuc Nghi Nguyen, Vilas Menon, Karel Svoboda, Matthew Kroll, Ed S. Lein, Peter A. Groblewski, Karla E. Hirokawa, Ali Cetin, Julie Pendergraft, Ian R. Wickersham, Tanya L. Daigle, Darren Bertagnolli, Jeff Goldy, Zizhen Yao, John W. Phillips, Michael Tieu, Loren L. Looger, Michael Hawrylycz, Aaron Szafer, Boaz P. Levi, Trygve E. Bakken, Nick Dee, Nadiya V. Shapovalova, Amy Bernard, Tamara Casper, Christof Koch, Kanan Lathia, and Lucas T. Graybuck

Subjects
Transcriptome, Cell type, medicine.anatomical_structure, Neocortex, Visual cortex, Cell, medicine, Excitatory postsynaptic potential, Biology, Inhibitory postsynaptic potential, Neuroscience, Motor cortex
Abstract

Neocortex contains a multitude of cell types segregated into layers and functionally distinct regions. To investigate the diversity of cell types across the mouse neocortex, we analyzed 12,714 cells from the primary visual cortex (VISp), and 9,035 cells from the anterior lateral motor cortex (ALM) by deep single-cell RNA-sequencing (scRNA-seq), identifying 116 transcriptomic cell types. These two regions represent distant poles of the neocortex and perform distinct functions. We define 50 inhibitory transcriptomic cell types, all of which are shared across both cortical regions. In contrast, 49 of 52 excitatory transcriptomic types were found in either VISp or ALM, with only three present in both. By combining single cell RNA-seq and retrograde labeling, we demonstrate correspondence between excitatory transcriptomic types and their region-specific long-range target specificity. This study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct regions of the mouse cortex.

Published
2017
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21. Neuropathological and transcriptomic characteristics of the aged brain

Author

Terri L. Gilbert, Thomas J. Montine, Aaron Szafer, Eiron Cudaback, Nick Dee, Christine Cuhaciyan, Xianwu Li, Kimberly A. Smith, Samuel R Josephsen, Tim A. Dolbeare, Paul K. Crane, Amy Bernard, Nadezhda Dotson, Michael Tieu, Fiona Griffin, Shannon E. Rose, Ed S. Lein, Jeff Goldy, Laura E. Gibbons, Julie Pendergraft, Felix Lee, Nivretta Thatra, Elaine Shen, Elizabeth Rha, Susan M. Sunkin, Garrett Gee, Lydia Potekhina, Nadia Postupna, Darren Bertagnolli, Andy J. Sodt, Nikolas L. Jorstad, Angela L. Guillozet-Bongaarts, Samantha Rice, Jeremy A. Miller, Natalie M Coleman, Zeb Haradon, Tsega Desta, David Rosen, Angela M. Wilson, Justin Johal, Shubhabrata Mukherjee, Kristopher Bickley, Anne Renz, Abharika Sapru, Robert Howard, Desiree A. Marshall, Tracy Lemon, Nika Hejazinia, Rachel A. Dalley, Shu Shi, Steve Horvath, Mindy L Chua, Aimee Schantz, Eric B. Larson, Allison Beller, Michael S. Fisher, Julie Nyhus, C. Dirk Keene, Lydia Ng, Kim Howard, Caroline Habel, Nathalie Gaudreault, Krissy Brouner, Leanne L Hellstern, Shiella Caldejon, Jose Melchor, Emily Sherfield, Chihchau L. Kuan, Mike Chapin, Richard G. Ellenbogen, Chris Barber, Florence Lai, and Eric Lee

Subjects
0301 basic medicine, Male, Amyloid beta, QH301-705.5, Science, Hippocampus, Disease, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, medicine, Dementia, Humans, Biology (General), Gene, Pathological, Aged, Aged, 80 and over, Cerebral Cortex, General Immunology and Microbiology, biology, business.industry, General Neuroscience, Gene Expression Profiling, aging, Cognition, General Medicine, Alzheimer's disease, medicine.disease, 3. Good health, Tools and Resources, 030104 developmental biology, biology.protein, gene expression, Medicine, Female, business, Neuroscience, 030217 neurology & neurosurgery, Human, dementia
Abstract

As more people live longer, age-related neurodegenerative diseases are an increasingly important societal health issue. Treatments targeting specific pathologies such as amyloid beta in Alzheimer’s disease (AD) have not led to effective treatments, and there is increasing evidence of a disconnect between traditional pathology and cognitive abilities with advancing age, indicative of individual variation in resilience to pathology. Here, we generated a comprehensive neuropathological, molecular, and transcriptomic characterization of hippocampus and two regions cortex in 107 aged donors (median = 90) from the Adult Changes in Thought (ACT) study as a freely-available resource (http://aging.brain-map.org/). We confirm established associations between AD pathology and dementia, albeit with increased, presumably aging-related variability, and identify sets of co-expressed genes correlated with pathological tau and inflammation markers. Finally, we demonstrate a relationship between dementia and RNA quality, and find common gene signatures, highlighting the importance of properly controlling for RNA quality when studying dementia.

Published
2017

22. An anatomically comprehensive atlas of the adult human brain transcriptome

Author

Susan M. Sunkin, Preston M. Cartagena, Robert Howard, Christian F. Beckmann, David Feng, Zeb Haradon, Chinh Dang, Angela L. Guillozet-Bongaarts, Derric Williams, Jeff Goldy, Yang Li, Rachel A. Dalley, Tracy Lemon, Darren Bertagnolli, Clifford R. Slaughterbeck, Simon Smith, Steve Horvath, Christof Koch, Amanda Ebbert, Andreas Jeromin, Paul Wohnoutka, Michael Hawrylycz, Andy J. Sodt, Beryl Swanson, H. Ronald Zielke, Zackery L. Riley, John A. Morris, Evan T. Lazarz, Chris Abajian, Allan R. Jones, Mike Chapin, Changkyu Lee, Pedro Adolfo Sequeira, Jay Schulkin, Christopher Lau, Jeremy A. Miller, Tim A. Dolbeare, Ling Li, Nick Dee, Sheana Parry, Barry Daly, Patrick D. Parker, Marty Kinnunen, Amy Bernard, Joshua J. Royall, Vance Faber, John G. Hohmann, Patrick R. Hof, Stephen M. Smith, Suvro Datta, Kimberly A. Smith, Elaine H. Shen, Caroline C. Overly, Ed S. Lein, Jayson M. Jochim, Benjamin W. Gregor, Melissa Reding, M. Mallar Chakravarty, Seth G. N. Grant, Lydia Ng, Jimmy Chong, Marquis P. Vawter, Daniel H. Geschwind, David R. Haynor, Andrew F. Boe, Louie N. van de Lagemaat, David R. Fowler, Magnetic Detection and Imaging, and Faculty of Science and Technology

Subjects
Adult, Male, Cell type, Calbindins, Dopamine, Neocortex, Biology, Hippocampus, Article, Transcriptome, 03 medical and health sciences, Mice, METIS-292322, 0302 clinical medicine, Atlases as Topic, S100 Calcium Binding Protein G, Species Specificity, Databases, Genetic, Transcriptional regulation, medicine, Animals, Humans, RNA, Messenger, Anatomy, Artistic, In Situ Hybridization, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, Internet, IR-83002, Multidisciplinary, Anatomical location, Gene Expression Profiling, Brain, Post-Synaptic Density, Human brain, Macaca mulatta, Gene expression profiling, medicine.anatomical_structure, Frontal lobe, Health, Neuroscience, 030217 neurology & neurosurgery
Abstract

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.

Published
2012

23. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project

Author

Nan Jiang, Alfonso Valencia, Rachel A. Harte, Abigail Woodroffe, Michael Seringhaus, Andrew Haydock, Eugene Davydov, Todd M. Lowe, Peggy J. Farnham, Robert E. Thurman, Tyler Alioto, Adam Ameur, Morgan Park, Roderic Guigó, Archana Thakkapallayil, Philipp Kapranov, Francis S. Collins, Donna Karolchik, Stefan Washietl, Kerstin Lindblad-Toh, Michael L. Tress, Barbara E. Stranger, Gregory M. Cooper, Kun Wang, Thomas R. Gingeras, Serafim Batzoglou, Peter D. Ellis, Annie Yang, Stylianos E. Antonarakis, Jonghwan Kim, Robert M. Andrews, W. James Kent, Kuo Ping Chiu, Madhavan Ganesh, Jason D. Lieb, Shane Neph, Albin Sandelin, Michael Hawrylycz, Eric S. Lander, Matthew T. Weirauch, Nick Goldman, Alexander E. Urban, Ian Bell, Anason S. Halees, Jan Komorowski, Webb Miller, Kandhadayar G. Srinivasan, Evelyn Cheung, David B. Jaffe, Peter J. Good, Gregory Lefebvre, Yuko Yoshinaga, Sylvain Foissac, Alexander W. Bruce, Mark Dickson, Christoph M. Koch, Antigone S. Dimas, Zhengdong D. Zhang, Matthew J. Oberley, Paul I.W. de Bakker, Arend Sidow, Xueqing Zhang, Molly Weaver, Jane Rogers, Jacquelyn R. Idol, Jeff Goldy, Haiyan Huang, William Stafford Noble, Angie S. Hinrichs, Sandeep Patel, David A. Nix, Lluís Armengol, Siew Woh Choo, Hong Sain Ooi, Sara Van Calcar, Ivan Adzhubei, Job Dekker, Sara J. Cooper, Hari Tammana, Valerie Maduro, Jason A. Greenbaum, Bing Ren, Sharon L. Squazzo, Jennifer C. McDowell, Chikatoshi Kai, Ivo L. Hofacker, Ian Dunham, Peter J. Bickel, Nancy Holroyd, Eduardo Eyras, Julien Lagarde, Fei Yao, Man Yu, Piero Carninci, Chia-Lin Wei, Alice C. Young, Yong Yu, Daryl J. Thomas, George Asimenos, Xiaoqin Xu, Galt P. Barber, Andrea Tanzer, Juan I. Montoya-Burgos, Sujit Dike, Nathan Day, Gregory E. Crawford, Michele Clamp, Todd Richmond, Nuria Lopez-Bigas, Vishwanath R. Iyer, Ewan Birney, Richard Humbert, Gary C. Hon, David Swarbreck, Xiaobin Guan, Sarah Wilcox, Nate Heintzman, Josep F. Abril, Elaine R. Mardis, Stefan Enroth, Charlie W.H. Lee, Nicholas Matthews, Benedict Paten, Robert Castelo, Michael A. Singer, Mousheng Xu, Chiou Yu Choo, Nancy F. Hansen, Elizabeth Rosenzweig, Patrick A. Navas, Jacqueline Chrast, Brett E. Johnson, Jan O. Korbel, Simon Whelan, Stephen Hartman, Ulas Karaoz, Ingileif B. Hallgrímsdóttir, David Haussler, Michael R. Brent, Jill Cheng, Gonçalo R. Abecasis, Ann S. Zweig, Sherman M. Weissman, Michael O. Dorschner, Jin Lian, Vinsensius B. Vega, Cordelia Langford, Alexandre Reymond, Mark Gerstein, Pawandeep Dhami, Ola Wallerman, Huaiyang Jiang, Lior Pachter, James Taylor, Eric A. Stone, David R. Inman, Yijun Ruan, Peter E. Newburger, Roland Green, Ari Löytynoja, Shelley Force Aldred, Alvaro Rada-Iglesias, Baishali Maskeri, Joel Rozowsky, Jorg Drenkow, Colin N. Dewey, Srinka Ghosh, Yutao Fu, Kayla E. Smith, Xavier Estivill, Donna M. Muzny, Christine P. Bird, Tim Hubbard, Jana Hertel, Kristin Missal, Neerja Karnani, Ericka M. Johnson, Nan Zhang, Zhou Zhu, Stephen C. J. Parker, Minmei Hou, Charlotte N. Henrichsen, Heather A. Hirsch, Caroline Manzano, Laura A. Liefer, Kim C. Worley, Robert Baertsch, Mark S. Guyer, Ross C. Hardison, Zheng Lian, Hiram Clawson, Leah O. Barrera, Manja Lindemeyer, James Cuff, Chunxu Qu, Jun Kawai, Jennifer Hillman-Jackson, Eric D. Green, Robert W. Blakesley, Abel Ureta-Vidal, Rhona K. Stuart, Fabio Pardi, Peter J. Sabo, Edward A. Sekinger, John S. Mattick, Ankit Malhotra, Taane G. Clark, James G. R. Gilbert, James C. Mullikin, Deyou Zheng, Robert M. Kuhn, Tae Hoon Kim, M. Geoff Rosenfeld, Kirsten Lee, Jörg Hackermüller, Oliver M. Dovey, Deanna M. Church, Kyle J. Munn, Peter F. Stadler, Phillippe Couttet, Claudia Fried, Jaafar N. Haidar, Kris A. Wetterstrand, Wing-Kin Sung, Paul G. Giresi, Jia Qian Wu, Ruth Taylor, David A. Wheeler, Zarmik Moqtaderi, Adam Siepel, Michael Snyder, Ian Holmes, Jun Liu, Olof Emanuelsson, Kevin Struhl, Saurabh Asthana, Akshay Bhinge, Adam Frankish, Yoshihide Hayashizaki, Ghia Euskirchen, Joel D. Martin, Robert S. Fulton, Ugrappa Nagalakshmi, Heike Fiegler, Gayle K. Clelland, Shane C. Dillon, Fidencio Neri, Elliott H. Margulies, Sean Davis, Mark Bieda, Tristan Frum, Michael S. Kuehn, Heather Trumbower, Pamela J. Thomas, Kazutoyo Osoegawa, Richard A. Gibbs, Emmanouil T. Dermitzakis, Julian L. Huppert, Richard K. Wilson, Tina Graves, Zhiping Weng, Anthony Shafer, Baoli Zhu, Christopher K. Glass, Patrick J. Boyle, Hennady P. Shulha, Maxim Koriabine, Christoph Flamm, David Vetrie, Nigel P. Carter, Patrick Ng, Peter Kraus, John A. Stamatoyannopoulos, George M. Weinstock, Tim Massingham, Jane M. Lin, Damian Keefe, Jean L. Chang, Shamil R. Sunyaev, Sergey Nikolaev, Kate R. Rosenbloom, Carine Wyss, Hua Cao, Keith D. James, Michael C. Zody, Gerard G. Bouffard, Atif Shahab, Nathan D. Trinklein, James B. Brown, Erica Sodergren, Xiaodong Zhao, Rosa Luna, Sante Gnerre, Paul Flicek, Joanna C. Fowler, Andrew D. Kern, Jakob Skou Pedersen, David C. King, Anindya Dutta, Elise A. Feingold, Richard M. Myers, Richard Sandstrom, Catherine Ucla, Thomas D. Tullius, Mikhail Nefedov, Claes Wadelius, Jennifer Harrow, Christopher M. Taylor, Xiaoling Zhang, Pieter J. de Jong, Dermitzakis, Emmanouil, and Reymond, Alexandre

Subjects
DNA Replication, RNA, Messenger/genetics, Chromatin Immunoprecipitation, Heterozygote, RNA, Untranslated, Transcription, Genetic, Systems biology, Histones/metabolism, RNA, Untranslated/genetics, Pilot Projects, Genomics, Computational biology, Regulatory Sequences, Nucleic Acid, Biology, ENCODE, Genome, Article, DNase-Seq, Histones, Evolution, Molecular, Exons/genetics, Humans, ddc:576.5, Transcription Factors/metabolism, RNA, Messenger, Conserved Sequence, Chromatin/genetics/metabolism, Genetics, Transcription, Genetic/ genetics, Multidisciplinary, Genome, Human, GENCODE, Genetic Variation, Exons, Chromatin, Genetic Variation/genetics, Regulatory Sequences, Nucleic Acid/ genetics, Human genome, Conserved Sequence/genetics, Transcription Initiation Site, Functional genomics, Genome, Human/ genetics, Transcription Factors, Protein Binding
Abstract

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view about chromatin structure has emerged, including its interrelationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded novel mechanistic and evolutionary insights about the functional landscape of the human genome. Together, these studies are defining a path forward to pursue a more-comprehensive characterisation of human genome function.

Published
2007

24. Mapping of Charcot-Marie-Tooth Disease Type 1C to Chromosome 16p Identifies a Novel Locus for Demyelinating Neuropathies

Author

Jeff Goldy, Phillip F. Chance, Alana S. Golden, Valerie A. Street, Thomas D. Bird, and Bruce L. Tempel

Subjects
Genetic Markers, Male, Candidate gene, congenital, hereditary, and neonatal diseases and abnormalities, Locus (genetics), Biology, Gene mutation, Atrophy, Gene mapping, Charcot-Marie-Tooth Disease, Report, Genetics, medicine, Humans, Genetics(clinical), Genetics (clinical), Genes, Dominant, Recombination, Genetic, Membrane Glycoproteins, Genetic heterogeneity, Haplotype, Chromosome Mapping, Exons, medicine.disease, Introns, Pedigree, Genetic marker, Female, Lod Score, Chromosomes, Human, Pair 16, Demyelinating Diseases
Abstract

Charcot-Marie-Tooth (CMT) neuropathy represents a genetically heterogeneous group of diseases affecting the peripheral nervous system. We report genetic mapping of the disease to chromosome 16p13.1-p12.3, in two families with autosomal dominant CMT type 1C (CMT1C). Affected individuals in these families manifest characteristic CMT symptoms, including high-arched feet, distal muscle weakness and atrophy, depressed deep-tendon reflexes, sensory impairment, slow nerve conduction velocities, and nerve demyelination. A maximal combined LOD score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in these two families localizes the CMT1C gene within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in these two pedigrees are not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. The epithelial membrane protein 2 gene (EMP2), which maps to chromosome 16p13.2, was evaluated as a candidate gene for CMT1C.

Published
2001

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