Massively Parallel Reporter Assays: Defining Functional Psychiatric Genetic Variants across Biological Contexts
作者： Bernard Mulvey , Tomas Lagunas , Joseph D. Dougherty
DOI: 10.1101/2020.02.02.931337
关键词:
摘要: Abstract Neuropsychiatric phenotypes have been long known to be influenced by heritable risk factors. The past decade of genetic studies confirmed this directly, revealing specific common and rare variants enriched in disease cohorts. However, the early hope for these studies—that only a small set genes would responsible given disorder—proved false. picture that has emerged is far more complex: disorder may myriad coding noncoding effect size, and/or but severe large many de novo. Noncoding genomic sequences harbor portion variants, which molecular functions cannot usually inferred from sequence alone. This creates substantial barrier understanding higher-order biological systems underlying risk. Fortunately, proliferation technologies—namely, scalable oligonucleotide synthesis, high-throughput RNA sequencing, CRISPR, CRISPR derivatives—have opened novel avenues experimentally identifying biologically significant en masse. These advances yielded an especially versatile technique adaptable large-scale functional assays variation both transcribed regulatory features: Massively Parallel Reporter Assays (MPRAs). MPRAs are powerful tools can used screen tens thousands predefined effects single experiment. approach several ideal features psychiatric genetics, remains underutilized field date. To emphasize opportunities MPRA holds dissecting polygenicity, we review here its applications date, discuss ability test variables implicated disorders, illustrate flexibility with proof-of-principle, vivo cell-type implementation assay, envision future outcomes applying computational experimental neurogenetics.
sci-hub.st 参考文章(107)
GTEx Consortium, Kristin G Ardlie, David S Deluca, Ayellet V Segrè, Timothy J Sullivan, Taylor R Young, Ellen T Gelfand, Casandra A Trowbridge, Julian B Maller, Taru Tukiainen, Monkol Lek, Lucas D Ward, Pouya Kheradpour, Benjamin Iriarte, Yan Meng, Cameron D Palmer, Tõnu Esko, Wendy Winckler, Joel N Hirschhorn, Manolis Kellis, Daniel G MacArthur, Gad Getz, Andrey A Shabalin, Gen Li, Yi-Hui Zhou, Andrew B Nobel, Ivan Rusyn, Fred A Wright, Tuuli Lappalainen, Pedro G Ferreira, Halit Ongen, Manuel A Rivas, Alexis Battle, Sara Mostafavi, Jean Monlong, Michael Sammeth, Marta Mele, Ferran Reverter, Jakob M Goldmann, Daphne Koller, Roderic Guigó, Mark I McCarthy, Emmanouil T Dermitzakis, Eric R Gamazon, Hae Kyung Im, Anuar Konkashbaev, Dan L Nicolae, Nancy J Cox, Timothée Flutre, Xiaoquan Wen, Matthew Stephens, Jonathan K Pritchard, Zhidong Tu, Bin Zhang, Tao Huang, Quan Long, Luan Lin, Jialiang Yang, Jun Zhu, Jun Liu, Amanda Brown, Bernadette Mestichelli, Denee Tidwell, Edmund Lo, Mike Salvatore, Saboor Shad, Jeffrey A Thomas, John T Lonsdale, Michael T Moser, Bryan M Gillard, Ellen Karasik, Kimberly Ramsey, Christopher Choi, Barbara A Foster, John Syron, Johnell Fleming, Harold Magazine, Rick Hasz, Gary D Walters, Jason P Bridge, Mark Miklos, Susan Sullivan, Laura K Barker, Heather M Traino, Maghboeba Mosavel, Laura A Siminoff, Dana R Valley, Daniel C Rohrer, Scott D Jewell, Philip A Branton, Leslie H Sobin, Mary Barcus, Liqun Qi, Jeffrey McLean, Pushpa Hariharan, Ki Sung Um, Shenpei Wu, David Tabor, Charles Shive, Anna M Smith, Stephen A Buia, Anita H Undale, Karna L Robinson, Nancy Roche, Kimberly M Valentino, Angela Britton, Robin Burges, Debra Bradbury, Kenneth W Hambright, John Seleski, Greg E Korzeniewski, Kenyon Erickson, Yvonne Marcus, Jorge Tejada, Mehran Taherian, Chunrong Lu, Margaret Basile, Deborah C Mash, Simona Volpi, Jeffery P Struewing, Gary F Temple, Joy Boyer, Deborah Colantuoni, Roger Little, Susan Koester, Latarsha J Carithers, Helen M Moore, Ping Guan, Carolyn Compton, Sherilyn J Sawyer, Joanne P Demchok, Jimmie B Vaught, Chana A Rabiner, Nicole C Lockhart, Kristin G Ardlie, Gad Getz, Fred A Wright, Manolis Kellis, Simona Volpi, Emmanouil T Dermitzakis, None, The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans Science. ,vol. 348, pp. 648- 660 ,(2015) , 10.1126/SCIENCE.1262110
Nathan Kopp, Sharlee Climer, Joseph D. Dougherty, Moving from capstones toward cornerstones: successes and challenges in applying systems biology to identify mechanisms of autism spectrum disorders Frontiers in Genetics. ,vol. 6, pp. 301- 301 ,(2015) , 10.3389/FGENE.2015.00301
J. D. Dougherty, S. E. Maloney, D. F. Wozniak, M. A. Rieger, L. Sonnenblick, G. Coppola, N. G. Mahieu, J. Zhang, J. Cai, G. J. Patti, B. S. Abrahams, D. H. Geschwind, N. Heintz, The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-Related Behaviors The Journal of Neuroscience. ,vol. 33, pp. 2732- 2753 ,(2013) , 10.1523/JNEUROSCI.4762-12.2013
Jacy L. Wagnon, Michael Briese, Wenzhi Sun, Connie L. Mahaffey, Tomaž Curk, Gregor Rot, Jernej Ule, Wayne N. Frankel, CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function. PLOS Genetics. ,vol. 8, pp. 1003067- ,(2012) , 10.1371/JOURNAL.PGEN.1003067
Jamie C. Kwasnieski, Christopher Fiore, Hemangi G. Chaudhari, Barak A. Cohen, High-throughput functional testing of ENCODE segmentation predictions Genome Research. ,vol. 24, pp. 1595- 1602 ,(2014) , 10.1101/GR.173518.114
John Lonsdale, Jeffrey Thomas, Mike Salvatore, Rebecca Phillips, Edmund Lo, Saboor Shad, Richard Hasz, Gary Walters, Fernando Garcia, Nancy Young, Barbara Foster, Mike Moser, Ellen Karasik, Bryan Gillard, Kimberley Ramsey, Susan Sullivan, Jason Bridge, Harold Magazine, John Syron, Johnelle Fleming, Laura Siminoff, Heather Traino, Maghboeba Mosavel, Laura Barker, Scott Jewell, Dan Rohrer, Dan Maxim, Dana Filkins, Philip Harbach, Eddie Cortadillo, Bree Berghuis, Lisa Turner, Eric Hudson, Kristin Feenstra, Leslie Sobin, James Robb, Phillip Branton, Greg Korzeniewski, Charles Shive, David Tabor, Liqun Qi, Kevin Groch, Sreenath Nampally, Steve Buia, Angela Zimmerman, Anna Smith, Robin Burges, Karna Robinson, Kim Valentino, Deborah Bradbury, Mark Cosentino, Norma Diaz-Mayoral, Mary Kennedy, Theresa Engel, Penelope Williams, Kenyon Erickson, Kristin Ardlie, Wendy Winckler, Gad Getz, David DeLuca, Daniel MacArthur, Manolis Kellis, Alexander Thomson, Taylor Young, Ellen Gelfand, Molly Donovan, Yan Meng, George Grant, Deborah Mash, Yvonne Marcus, Margaret Basile, Jun Liu, Jun Zhu, Zhidong Tu, Nancy J Cox, Dan L Nicolae, Eric R Gamazon, Hae Kyung Im, Anuar Konkashbaev, Jonathan Pritchard, Matthew Stevens, Timothèe Flutre, Xiaoquan Wen, Emmanouil T Dermitzakis, Tuuli Lappalainen, Roderic Guigo, Jean Monlong, Michael Sammeth, Daphne Koller, Alexis Battle, Sara Mostafavi, Mark McCarthy, Manual Rivas, Julian Maller, Ivan Rusyn, Andrew Nobel, Fred Wright, Andrey Shabalin, Mike Feolo, Nataliya Sharopova, Anne Sturcke, Justin Paschal, James M Anderson, Elizabeth L Wilder, Leslie K Derr, Eric D Green, Jeffery P Struewing, Gary Temple, Simona Volpi, Joy T Boyer, Elizabeth J Thomson, Mark S Guyer, Cathy Ng, Assya Abdallah, Deborah Colantuoni, Thomas R Insel, Susan E Koester, A Roger Little, Patrick K Bender, Thomas Lehner, Yin Yao, Carolyn C Compton, Jimmie B Vaught, Sherilyn Sawyer, Nicole C Lockhart, Joanne Demchok, Helen F Moore, The Genotype-Tissue Expression (GTEx) project Nature Genetics. ,vol. 45, pp. 580- 585 ,(2013) , 10.1038/NG.2653
J. C. Kwasnieski, I. Mogno, C. A. Myers, J. C. Corbo, B. A. Cohen, Complex effects of nucleotide variants in a mammalian cis-regulatory element Proceedings of the National Academy of Sciences of the United States of America. ,vol. 109, pp. 19498- 19503 ,(2012) , 10.1073/PNAS.1210678109
Magalie Penaud-Budloo, Caroline Le Guiner, Ali Nowrouzi, Alice Toromanoff, Yan Chérel, Pierre Chenuaud, Manfred Schmidt, Christof Von Kalle, Fabienne Rolling, Philippe Moullier, Richard O Snyder, None, Adeno-Associated Virus Vector Genomes Persist as Episomal Chromatin in Primate Muscle Journal of Virology. ,vol. 82, pp. 7875- 7885 ,(2008) , 10.1128/JVI.00649-08
Anshul Kundaje, Wouter Meuleman, Jason Ernst, Misha Bilenky, Angela Yen, Alireza Heravi-Moussavi, Pouya Kheradpour, Zhizhuo Zhang, Jianrong Wang, Michael J Ziller, Viren Amin, John W Whitaker, Matthew D Schultz, Lucas D Ward, Abhishek Sarkar, Gerald Quon, Richard S Sandstrom, Matthew L Eaton, Yi-Chieh Wu, Andreas R Pfenning, Xinchen Wang, Melina Claussnitzer, Yaping Liu, Cristian Coarfa, R Alan Harris, Noam Shoresh, Charles B Epstein, Elizabeta Gjoneska, Danny Leung, Wei Xie, R David Hawkins, Ryan Lister, Chibo Hong, Philippe Gascard, Andrew J Mungall, Richard Moore, Eric Chuah, Angela Tam, Theresa K Canfield, R Scott Hansen, Rajinder Kaul, Peter J Sabo, Mukul S Bansal, Annaick Carles, Jesse R Dixon, Kai-How Farh, Soheil Feizi, Rosa Karlic, Ah-Ram Kim, Ashwinikumar Kulkarni, Daofeng Li, Rebecca Lowdon, GiNell Elliott, Tim R Mercer, Shane J Neph, Vitor Onuchic, Paz Polak, Nisha Rajagopal, Pradipta Ray, Richard C Sallari, Kyle T Siebenthall, Nicholas A Sinnott-Armstrong, Michael Stevens, Robert E Thurman, Jie Wu, Bo Zhang, Xin Zhou, Arthur E Beaudet, Laurie A Boyer, Philip L De Jager, Peggy J Farnham, Susan J Fisher, David Haussler, Steven JM Jones, Wei Li, Marco A Marra, Michael T McManus, Shamil Sunyaev, James A Thomson, Thea D Tlsty, Li-Huei Tsai, Wei Wang, Robert A Waterland, Michael Q Zhang, Lisa H Chadwick, Bradley E Bernstein, Joseph F Costello, Joseph R Ecker, Martin Hirst, Alexander Meissner, Aleksandar Milosavljevic, Bing Ren, John A Stamatoyannopoulos, Ting Wang, Manolis Kellis, None, Integrative analysis of 111 reference human epigenomes Nature. ,vol. 518, pp. 317- 330 ,(2015) , 10.1038/NATURE14248
Cosmas D Arnold, Daniel Gerlach, Christoph Stelzer, Łukasz M Boryń, Martina Rath, Alexander Stark, None, Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science. ,vol. 339, pp. 1074- 1077 ,(2013) , 10.1126/SCIENCE.1232542