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Somatic mosaicism in schizophrenia brains reveals prenatal mutational processes

SCIENCE 2024年第6718期386卷 217-224页

作者： Maury, Eduardo A. Jones, Attila Seplyarskiy, Vladimir Nguyen, Thanh Thanh L. Rosenbluh, Chaggai Bae, Taejong Wang, Yifan Abyzov, Alexej Khoshkhoo, Sattar Chahine, Yasmine Zhao, Sijing Venkatesh, Sanan Root, Elise Voloudakis, Georgios Roussos, Panagiotis Park, Peter J. Akbarian, Schahram Brennand, Kristen Reilly, Steven Lee, Eunjung A. Sunyaev, Shamil R. Walsh, Christopher A. Chess, Andrew Boston Childrens Hosp Manton Ctr Orphan Dis Div Genet & Genom Boston MA 02118 USA Harvard Med Sch Harvard MIT MD PhD Program Bioinformat & Integrat Genom Program Boston MA USA Broad Inst MIT & Harvard Program Med & Populat Genet Cambridge MA 02138 USA Icahn Sch Med Mt Sinai Dept Cell Dev & Regenerat Biol New York NY 10029 USA Icahn Sch Med Mt Sinai Dept Genet & Genom Sci New York NY 10029 USA Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Harvard Med Sch Brigham & Womens Hosp Div Genet Boston MA 02115 USA Yale Sch Med Dept Genet New Haven CT 06520 USA Yale Sch Med Dept Psychiat New Haven CT 06510 USA Mayo Clin Ctr Individualized Med Dept Quantitat Hlth Sci Rochester MN 55905 USA Brigham & Womens Hosp Dept Neurol Boston MA 02115 USA Icahn Sch Med Mt Sinai Ctr Dis Neurogenom New York NY 10029 USA Icahn Sch Med Mt Sinai Friedman Brain Inst Dept Psychiat New York NY 10029 USA Mt Sinai Friedman Brain Inst Dept Neurosci New York NY 10029 USA Harvard Med Sch Dept Pediat & Neurol Boston MA 02115 USA Boston Childrens Hosp Howard Hughes Med Inst Boston MA 02115 USA

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239x) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.

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Mapping a functional cancer genome atlas of tumor suppressors in mouse liver using AAV-CRISPR-mediated direct in vivo screening

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SCIENCE ADVANCES 2018年第2期4卷 5508-5508页

作者： Wang, Guangchuan Chow, Ryan D. Ye, Lupeng Guzman, Christopher D. Dai, Xiaoyun Dong, Matthew B. Zhang, Feng Sharp, Phillip A. Platt, Randall J. Chen, Sidi Yale Univ Sch Med Dept Genet New Haven CT 06510 USA Yale Univ Sch Med Syst Biol Inst 850 West Campus Dr West Haven CT 06516 USA Yale Univ Sch Med MD PhD Program New Haven CT 06510 USA Yale Univ Sch Med Immunobiol Program New Haven CT 06510 USA Yale Univ Dept Immunobiol Sch Med New Haven CT 06510 USA Broad Inst Massachusetts Inst Technol MIT 75 Ames St Cambridge MA 02142 USA Harvard Univ 75 Ames St Cambridge MA 02142 USA MIT Dept Biol Engn Cambridge MA 02142 USA MIT Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol Cambridge MA 02139 USA Swiss Fed Inst Technol Dept Biosyst Sci & Engn Mattenstr 26 CH-4058 Basel Switzerland Univ Basel Dept Chem Peterspl 1 CH-4003 Basel Switzerland Yale Univ Biol & Biomed Sci Program Sch Med West Haven CT 06516 USA Yale Univ Comprehens Canc Ctr Sch Med West Haven CT 06516 USA Yale Univ Stem Cell Ctr Sch Med West Haven CT 06516 USA

Cancer genomics consortia have charted the landscapes of numerous human cancers. Whereas somemutations were found in classical oncogenes and tumor suppressors, others have not yet been functionally studied in vivo. To date, a comprehensive assessment of how these genes influence oncogenesis is lacking. We performed direct high-throughput in vivo mapping of functional variants in an autochthonous mouse model of cancer. Using adeno-associated viruses (AAVs) carrying a single-guide RNA (sgRNA) library targeting putative tumor suppressor genes significantly mutated in human cancers, we directly pool-mutagenized the livers of Cre-inducible CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (Cas9) mice. All mice that received the AAV-mTSG library developed liver cancer and died within 4 months. We used molecular inversion probe sequencing of the sgRNA target sites to chart the mutational landscape of these tumors, revealing the functional consequence of multiple variants in driving liver tumorigenesis in immunocompetent mice. AAV-mediated autochthonous CRISPR screens provide a powerful means for mapping a provisional functional cancer genome atlas of tumor suppressors in vivo.

关键词： Mapping

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Custom CRISPR-Cas9 PAM variants via scalable engineering and machine learning

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Nature 2025年 2025 Apr 22页

作者： Rachel A Silverstein Nahye Kim Ann-Sophie Kroell Russell T Walton Justin Delano Rossano M Butcher Martin Pacesa Blaire K Smith Kathleen A Christie Leillani L Ha Ronald J Meis Aaron B Clark Aviv D Spinner Cicera R Lazzarotto Yichao Li Azusa Matsubara Elizabeth O Urbina Gary A Dahl Bruno E Correia Debora S Marks Shengdar Q Tsai Luca Pinello Suk See De Ravin Qin Liu Benjamin P Kleinstiver PhD Program in Biological and Biomedical Sciences Harvard Medical School Boston MA USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. Department of Pathology Massachusetts General Hospital Boston MA USA. Department of Pathology Harvard Medical School Boston MA USA. Institute of Pharmacy and Molecular Biotechnology (IPMB) Faculty of Engineering Sciences Heidelberg University Heidelberg Germany. Department of Biomedical Informatics Harvard Medical School Boston MA USA. Molecular Pathology Unit Massachusetts General Hospital Charlestown MA USA. Krantz Family Center for Cancer Research Massachusetts General Hospital Charlestown Charlestown MA USA. Broad Institute of Harvard and MIT Cambridge MA USA. Ocular Genomics Institute Massachusetts Eye and Ear Boston MA USA. Department of Ophthalmology Harvard Medical School Boston MA USA. Laboratory of Protein Design and Immunoengineering École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics Lausanne Switzerland. CELLSCRIPTTM Madison WI USA. Department of Systems Biology Harvard Medical School Boston MA USA. Department of Hematology St. Jude Children's Research Hospital Memphis TN USA. Laboratory of Clinical Immunology and Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD USA. Center for Genomic Medicine Massachusetts General Hospital Boston MA USA. bkleinstiver@mgh.harvard.edu. Department of Pathology Massachusetts General Hospital Boston MA USA. bkleinstiver@mgh.harvard.edu. Department of Pathology Harvard Medical School Boston MA USA. bkleinstiver@mgh.harvard.edu.

Engineering and characterizing proteins can be time-consuming and cumbersome, motivating the development of generalist CRISPR-Cas enzymes to enable diverse genome editing applications. However, such enzymes have caveats such as an increased risk of off-target editing. To enable scalable reprogramming of Cas9 enzymes, here we combined high-throughput protein engineering with machine learning (ML) to derive bespoke editors more uniquely suited to specific targets. Via structure/function-informed saturation mutagenesis and bacterial selections, we obtained nearly 1,000 engineered SpCas9 enzymes and characterized their protospacer-adjacent motif (PAM) requirements to train a neural network that relates amino acid sequence to PAM specificity. By utilizing the resulting PAM ML algorithm (PAMmla) to predict the PAMs of 64 million SpCas9 enzymes, we identified efficacious and specific enzymes that outperform evolution-based and engineered SpCas9 enzymes as nucleases and base editors in human cells while reducing off-targets. An in silico directed evolution method enables user-directed Cas9 enzyme design, including for allele-selective targeting of the RHO P23H allele in human cells and mice. Together, PAMmla integrates ML and protein engineering to curate a catalog of SpCas9 enzymes with distinct PAM requirements, and motivates the use of efficient and safe bespoke Cas9 enzymes instead of generalist enzymes for various applications.

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Genome-Scale Screen Reveals Genes Required for Lenalidomide-Mediated Degradation of Aiolos By CRL4-CRBN

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BLOOD 2016年第22期128卷 5139-5139页

作者： Sievers, Quinlan Gasser, Jessica Cowley, Glenn Doench, John G. Fischer, Eric Ebert, Benjamin L. Broad Inst Harvard MIT MD PhD Program Cambridge MA USA Broad Inst Cambridge MA USA Broad Inst Massachusetts Inst Technol Harvard Med Sch Cambridge MA USA Dana Farber Chem Biol Boston MA USA Brigham & Womens Hosp Div Hematol Boston MA USA

5139

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Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging

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NATURE COMMUNICATIONS 2023年第1期14卷 7034页

作者： Nithianandam, Vanitha Bukhari, Hassan Leventhal, Matthew J. Battaglia, Rachel A. Dong, Xianjun Fraenkel, Ernest Feany, Mel B. Harvard Med Sch Brigham & Womens Hosp Dept Pathol Boston MA 02115 USA Aligning Sci Parkinsons ASAP Collaborat Res Networ Chevy Chase MD 20815 USA MIT Dept Biol Engn Cambridge MA USA MIT PhD Program Computat & Syst Biol Cambridge MA USA Brigham & Womens Hosp Genom & Bioinformat Hub Boston MA USA

A beta peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimer's disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recover the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We perform comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We find an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically define a role for Appl in regulating autophagy through TGF beta signaling and document the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimer's disease.

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Probabilistic Genotype-Phenotype Maps Reveal Mutational Robustness of RNA Folding, Spin Glasses, and Quantum Circuits

arXiv

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arXiv 2023年

作者： Sappington, Anna Mohanty, Vaibhav Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology CambridgeMA02139 United States Program for Health Sciences and Technology Harvard Medical School BostonMA02115 United States Massachusetts Institute of Technology CambridgeMA02139 United States Harvard/MIT MD-PhD Program Harvard Medical School BostonMA02115 United States Department of Chemistry and Chemical Biology Harvard University CambridgeMA02138 United States

Recent studies of genotype-phenotype (GP) maps have reported universally enhanced phenotypic robustness to genotype mutations, a feature essential to evolution. Virtually all of these studies make a simplifying assumption that each genotype—represented as a sequence—maps deterministically to a single phenotype, such as a discrete structure. Here, we introduce probabilistic genotype-phenotype (PrGP) maps, where each genotype maps to a vector of phenotype probabilities, as a more realistic and universal language for investigating robustness in a variety of physical, biological, and computational systems. We study three model systems to show that PrGP maps offer a generalized framework which can handle uncertainty emerging from various physical sources: (1) thermal fluctuation in RNA folding, (2) external field disorder in spin glass ground state finding, and (3) superposition and entanglement in quantum circuits, which are realized experimentally on IBM quantum computers. In all three cases, we observe a novel biphasic robustness scaling which is enhanced relative to random expectation for more frequent phenotypes and approaches random expectation for less frequent phenotypes. We derive an analytical theory for the behavior of PrGP robustness, and we demonstrate that the theory is highly predictive of empirical robustness. © 2023, CC BY.

关键词： Quantum computers

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The Diverse Genetic Landscape of Neurodevelopmental Disorders

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Genomics and Human Genetics 1000年第1期15卷 195-213页

作者： Wen F. Hu Maria H. Chahrour Christopher A. Walsh 3Harvard-MIT MD-PhD MSTP Program 2Program in Neuroscience 1Division of Genetics and Genomics Department of Medicine Manton Center for Orphan Disease Research and Howard Hughes Medical Institute Boston Children's Hospital Boston Massachusetts 02115 email: wenfanhu@hms.harvard.edu maria.chahrour@childrens.harvard.edu christopher.walsh@childrens.harvard.edu 6Autism Consortium Boston Massachusetts 02115 4Department of Pediatrics 5Department of Neurology Harvard Medical School Boston Massachusetts 02115

Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.

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Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability

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NATURE NEUROSCIENCE 2021年第3期24卷 437-448页

作者： Boulting, Gabriella L. Durresi, Ershela Ataman, Bulent Sherman, Maxwell A. Mei, Kevin Harmin, David A. Carter, Ava C. Hochbaum, Daniel R. Granger, Adam J. Engreitz, Jesse M. Hrvatin, Sinisa Blanchard, Michael R. Yang, Marty G. Griffith, Eric C. Greenberg, Michael E. Harvard Med Sch Dept Neurobiol Boston MA 02115 USA Harvard Med Sch MD PhD Program Boston MA 02115 USA Brigham & Womens Hosp Div Genet 75 Francis St Boston MA 02115 USA Brigham & Womens Hosp Ctr Data Sci 75 Francis St Boston MA 02115 USA MIT Comp Sci & Artificial Intelligence Lab 77 Massachusetts Ave Cambridge MA 02139 USA Stanford Univ Dept Genet Sch Med Stanford CA 94305 USA Lucile Packard Childrens Hosp BASE Initiat Betty Irene Moore Childrens Heart Ctr Stanford CA USA Harvard Med Sch Dept Neurobiol Neurobiol Imaging Facil Boston MA 02115 USA NYU Langone Med Ctr Dept Internal Med New York NY USA NYU Sch Med New York NY USA

Boulting et al. profile activity-dependent gene expression and regulatory elements in human induced pluripotent stem cell-derived GABAergic neurons and uncover a possible role for calcium-responsive gene promoters of these neurons in autism risk. Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk.

关键词： Autism spectrum disorders Gene expression profiling Gene regulation Genetics of the nervous system Molecular neuroscience

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The choroid plexus synergizes with immune cells during neuroinflammation

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CELL 2024年第18期187卷 4946-4963.e17页

作者： Xu, Huixin Lotfy, Peter Gelb, Sivan Pragana, Aja Hehnly, Christine Byer, Lillian I. J. Shipley, Frederick B. Zawadzki, Miriam E. Cui, Jin Deng, Liwen Taylor, Milo Webb, Mya Lidov, Hart G. W. Andermann, Mark L. Chiu, Isaac M. Ordovas-Montanes, Jose Lehtinen, Maria K. Boston Childrens Hosp Dept Pathol Boston MA 02115 USA Harvard Med Sch Boston MA 02115 USA Boston Childrens Hosp Div Gastroenterol Hepatol & Nutr Boston MA 02115 USA Harvard Med Sch Grad Program Biol & Biomed Sci Boston MA 02115 USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Univ Grad Program Biophys Cambridge MA 02138 USA Harvard Med Sch Harvard MD PhD Program Boston MA 02115 USA Harvard Med Sch Blavatnik Inst Dept Immunol Boston MA 02115 USA Harvard Univ Harvard Coll Cambridge MA 02138 USA Beth Israel Deaconess Med Ctr Dept Med Div Endocrinol Diabet & Metab Boston MA 02215 USA Harvard Med Sch Dept Neurobiol Boston MA 02115 USA Harvard Stem Cell Inst Cambridge MA 02138 USA Ragon Inst MGH MIT & Harvard Cambridge MA 02139 USA

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier.

关键词： choroid plexus blood-CSF barrier bacterial infection neuroinflammation immune recruitment epithelial cells epiplexus macrophages adhesion molecules colony-stimulating factor 1

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Early role for a Na⁺,K⁺-ATPase (ATP1A3) in brain development

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2021年第25期118卷 1页

作者： Smith, Richard S. Florio, Marta Akula, Shyam K. Neil, Jennifer E. Wang, Yidi Hill, R. Sean Goldman, Melissa Mullally, Christopher D. Reed, Nora Bello-Espinosa, Luis Flores-Sarnat, Laura Monteiro, Fabiola Paoli Erasmo, Casella B. Pinto, Filippo Morava, Eva Barkovich, A. James Gonzalez-Heydrich, Joseph Brownstein, Catherine A. McCarroll, Steven A. Walsh, Christopher A. Boston Childrens Hosp Manton Ctr Orphan Dis Res Div Genet & Genom Howard Hughes Med Insitute Boston MA 02115 USA Harvard Med Sch Broad Inst MIT & Harvard Dept Pediat & Neurol Boston MA 02115 USA Harvard Med Sch Dept Genet Boston MA 02115 USA Broad Inst & MIT Harvard Stanley Ctr Psychiat Res Cambridge MA 02142 USA Harvard Med Sch Harvard MD PhD Program Program Neurosci Boston MA 02115 USA Arnold Palmer Hosp Children Orlando FL 32806 USA Univ Calgary Owerko Ctr Dept Paediat & Clin Neurosci Calgary AB T2N IN4 Canada Alberta Childrens Hosp Res Inst Calgary AB T2N 1N4 Canada Mendel Genom Anal BR-04013000 Sao Paulo Brazil Childrens Inst Hosp Clin BR-05403000 Sao Paulo Brazil Mayo Clin Ctr Individualized Med Rochester MN 55905 USA Mayo Clin Dept Clin Genom Rochester MN 55905 USA Univ Calif San Francisco Benioff Childrens Hosp Dept Radiol San Francisco CA 94117 USA Univ Calif San Francisco Benioff Childrens Hosp Dept Pediat San Francisco CA 94117 USA Univ Calif San Francisco Benioff Childrens Hosp Dept Pediat San Francisco CA 94117 USA Univ Calif San Francisco Benioff Childrens Hosp Dept Neurol San Francisco CA 94143 USA Harvard Med Sch Boston Childrens Hosp Dept Psychiat Boston MA 02115 USA

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase alpha-subunit. Here, we describe ATP1A3 variants encoding dysfunctional alpha 3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of similar to 125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled -52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin inter neurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific alpha-beta isoform combinations, including alpha 3-beta 1 in excitatory neurons and alpha 3-beta 2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for alpha 3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

关键词： cortex development ATP1A3 developmental channelopathy polymicrogyria cortical malformation

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