Mapping recurrent mosaic copy number variation in human neurons
Chen Sun, Kunal Kathuria, Sarah B. Emery, Byung-Jun Kim, Ian Burbulis, Joo Heon Shin, Brain Somatic Mosaicism Network, Joseph G. Gleeson, Martin W. Breuss, Xiaoxu Yang, Danny Antaki, Changuk Chung, Dan Averbuj, Laurel Ball, Subhojit Roy, Daniel R. Weinberger, Andrew E. Jaffe, Apuã C.M. Paquola, Jennifer A. Erwin, Richard E. Straub, Rujuta Narurkar, Gary W. Mathern, Christopher A. Walsh, Alice Lee, August Yue Huang, Alissa M. D’Gama, Caroline Dias, Eduardo A. Maury, Javier Ganz, Michael A. Lodato, Michael Miller, Pengpeng Li, Rachel E. Rodin, Rebeca Borges-Monroy, Robert Hill, Sara Bizzotto, Sattar Khoshkhoo, Sonia Kim, Zinan Zhou, Peter J. Park, Alison R. Barton, Alon Galor, Chong Chu, Craig L. Bohrson, D. Gulhan, Elaine T. Lim, Eun‐Cheon Lim, Giorgio Melloni, Isidro Cortes, Jake Lee, Joe Luquette, Lixing Yang, Maxwell A. Sherman, Michael E. Coulter, Min‐Seok Kwon, Semin Lee, Soo In Lee, Vinary Viswanadham, Yanmei Dou, Andrew Chess, Attila Jones, Chaggai Rosenbluh, Schahram Akbarian, Ben Langmead, Jeremy Thorpe, Sean Cho, Alexej Abyzov, Taejeong Bae, Yeongjun Jang, Yifan Wang, Cindy Molitor, Mette A. Peters, Fred H. Gage, Meiyan Wang, Patrick Reed, Sara B. Linker, Alexander E. Urban, Bo Zhou, Reenal Pattni, Xiaowei Zhu, Aitor Serres Amero, David Juan, Inna Povolotskaya, Irene Lobón, Manuel Solis Moruno, Raquel García, Tomàs Marquès‐Bonet, Eduardo Soriano, John V. Moran, Diane A. Flasch, Trenton J. Frisbie, Huira C. Kopera, John B. Moldovan, Kenneth Y. Kwan, Ryan E. Mills, Weichen Zhou, Xuefang Zhao, Aakrosh Ratan, Flora M. Vaccarino, Adriana Cherskov
Abstract
When somatic cells acquire complex karyotypes, they often are removed by the immune system. Mutant somatic cells that evade immune surveillance can lead to cancer. Neurons with complex karyotypes arise during neurotypical brain development, but neurons are almost never the origin of brain cancers. Instead, somatic mutations in neurons can bring about neurodevelopmental disorders, and contribute to the polygenic landscape of neuropsychiatric and neurodegenerative disease. A subset of human neurons harbors idiosyncratic copy number variants (CNVs, "CNV neurons"), but previous analyses of CNV neurons are limited by relatively small sample sizes. Here, we develop an allele-based validation approach, SCOVAL, to corroborate or reject read-depth based CNV calls in single human neurons. We apply this approach to 2,125 frontal cortical neurons from a neurotypical human brain. SCOVAL identifies 226 CNV neurons, which include a subclass of 65 CNV neurons with highly aberrant karyotypes containing whole or substantial losses on multiple chromosomes. Moreover, we find that CNV location appears to be nonrandom. Recurrent regions of neuronal genome rearrangement contain fewer, but longer, genes.