Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
Taejeong Bae, Liana Fasching, Yifan Wang, Joo Heon Shin, Milovan Šuvakov, Yeongjun Jang, Scott Norton, Caroline Dias, Jessica Mariani, Alexandre Jourdon, Feinan Wu, Arijit Panda, Reenal Pattni, Yasmine Chahine, Rebecca C. Yeh, Rosalinda C. Roberts, Anita Hüttner, Joel E. Kleinman, Thomas M. Hyde, Richard E. Straub, Christopher A. Walsh, Brain Somatic Mosaicism Network§, Alexander E. Urban, James F. Leckman, Daniel R. Weinberger, Flora M. Vaccarino, Alexej Abyzov, Christopher A. Walsh, Peter J. Park, Nenad Šestan, Daniel R. Weinberger, John V. Moran, Fred H. Gage, Flora M. Vaccarino, Joseph G. Gleeson, Gary W. Mathern, Eric Courchesne, Subhojit Roy, Andrew Chess, Schahram Akbarian, Sara Bizzotto, Michael E. Coulter, Caroline Dias, Alissa M. D’Gama, Javier Ganz, Robert Hill, August Yue Huang, Sattar Khoshkhoo, Sonia Kim, Alice Lee, Michael A. Lodato, Eduardo A. Maury, Michael Miller, Rebeca Borges-Monroy, Rachel E. Rodin, Zinan Zhou, Craig L. Bohrson, Chong Chu, Isidro Cortés‐Ciriano, Yanmei Dou, Alon Galor, D. Gulhan, Min‐Seok Kwon, Joe Luquette, Maxwell A. Sherman, Vinay Viswanadham, Attila Jones, Chaggai Rosenbluh, Sean Cho, Ben Langmead, Jeremy Thorpe, Jennifer A. Erwin, Andrew E. Jaffe, Michael J. McConnell, Rujuta Narurkar, Apuã C.M. Paquola, Jooheon Shin, Richard E. Straub, Alexej Abyzov, Taejeong Bae, Yeongjun Jang, Yifan Wang, Cindy Molitor, Mette A. Peters, Sara B. Linker, Patrick Reed, Meiyan Wang, Alexander E. Urban, Bo Zhou, Xiaowei Zhu, Reenal Pattni, Aitor Serres Amero, David Juan, Irene Lobón, Tomàs Marquès‐Bonet, Manuel Solis Moruno, Raquel García Pérez, Inna Povolotskaya, Eduardo Soriano, Danny Antaki
Abstract
We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.