%0 Journal Article %J Cell %D 2020 %T Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. %A Satterstrom, F Kyle %A Kosmicki, Jack A %A Wang, Jiebiao %A Breen, Michael S %A De Rubeis, Silvia %A An, Joon-Yong %A Peng, Minshi %A Collins, Ryan %A Grove, Jakob %A Klei, Lambertus %A Stevens, Christine %A Reichert, Jennifer %A Mulhern, Maureen S %A Artomov, Mykyta %A Gerges, Sherif %A Sheppard, Brooke %A Xu, Xinyi %A Bhaduri, Aparna %A Norman, Utku %A Brand, Harrison %A Schwartz, Grace %A Nguyen, Rachel %A Guerrero, Elizabeth E %A Dias, Caroline %A Betancur, Catalina %A Cook, Edwin H %A Gallagher, Louise %A Gill, Michael %A Sutcliffe, James S %A Thurm, Audrey %A Zwick, Michael E %A Børglum, Anders D %A State, Matthew W %A Cicek, A Ercument %A Talkowski, Michael E %A Cutler, David J %A Devlin, Bernie %A Sanders, Stephan J %A Roeder, Kathryn %A Daly, Mark J %A Buxbaum, Joseph D %K Autistic Disorder %K Case-Control Studies %K Cell Lineage %K Cerebral Cortex %K Cohort Studies %K Exome %K Female %K Gene Expression Regulation, Developmental %K Gene Frequency %K Genetic Predisposition to Disease %K Humans %K Male %K Mutation, Missense %K Neurobiology %K Neurons %K Phenotype %K Sex Factors %K Single-Cell Analysis %K Whole Exome Sequencing %X

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

%B Cell %V 180 %P 568-584.e23 %8 2020 02 06 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31981491?dopt=Abstract %R 10.1016/j.cell.2019.12.036 %0 Journal Article %J Neuron %D 2017 %T cTag-PAPERCLIP Reveals Alternative Polyadenylation Promotes Cell-Type Specific Protein Diversity and Shifts Araf Isoforms with Microglia Activation. %A Hwang, Hun-Way %A Saito, Yuhki %A Park, Christopher Y %A Blachère, Nathalie E %A Tajima, Yoko %A Fak, John J %A Zucker-Scharff, Ilana %A Darnell, Robert B %K Animals %K Antigens, Neoplasm %K Astrocytes %K Brain %K Cells, Cultured %K Female %K Humans %K Male %K Mice %K Microglia %K Nerve Tissue Proteins %K Neuro-Oncological Ventral Antigen %K Neurons %K Organ Specificity %K Polyadenylation %K Polypyrimidine Tract-Binding Protein %K Protein Isoforms %K Protein Serine-Threonine Kinases %K RNA-Binding Proteins %X

Alternative polyadenylation (APA) is increasingly recognized to regulate gene expression across different cell types, but obtaining APA maps from individual cell types typically requires prior purification, a stressful procedure that can itself alter cellular states. Here, we describe a new platform, cTag-PAPERCLIP, that generates APA profiles from single cell populations in intact tissues; cTag-PAPERCLIP requires no tissue dissociation and preserves transcripts in native states. Applying cTag-PAPERCLIP to profile four major cell types in the mouse brain revealed common APA preferences between excitatory and inhibitory neurons distinct from astrocytes and microglia, regulated in part by neuron-specific RNA-binding proteins NOVA2 and PTBP2. We further identified a role of APA in switching Araf protein isoforms during microglia activation, impacting production of downstream inflammatory cytokines. Our results demonstrate the broad applicability of cTag-PAPERCLIP and a previously undiscovered role of APA in contributing to protein diversity between different cell types and cellular states within the brain.

%B Neuron %V 95 %P 1334-1349.e5 %8 2017 Sep 13 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/28910620?dopt=Abstract %R 10.1016/j.neuron.2017.08.024