研究人员分析了131个人类大脑（44个神经型，19个抽动症患者，9个精神分裂症患者，和59个自闭症患者）在全基因组测序后的体细胞突变，深度超过200倍。通常情况下，大脑有20至60个可检测到的单核苷酸突变，但约6%的大脑有数百个体细胞突变。高突变性与年龄和与癌症有关的基因的破坏性突变有关，在一些大脑中，反映了体内的克隆性扩增。可能在发育过程中产生的体细胞复制，在大约5%的正常和患病的大脑中被发现，反映了背景突变的发生。
患有自闭症的大脑与突变有关，这些突变在发育中的大脑增强子样区域产生了推定的转录因子结合模体。排名靠前的受影响模体与MEIS（骨髓异位病毒整合位点）转录因子相对应，表明它们参与基因调控和自闭症之间的潜在联系。
附：英文原文
Title: Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
Author: Taejeong Bae, Liana Fasching, Yifan Wang, Joo Heon Shin, Milovan Suvakov, Yeongjun Jang, Scott Norton, Caroline Dias, Jessica Mariani, Alexandre Jourdon, Feinan Wu, Arijit Panda, Reenal Pattni, Yasmine Chahine, Rebecca Yeh, Rosalinda C. Roberts, Anita Huttner, 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 Sestan, Daniel Weinberger, John V. Moran, Fred H. Gage, Flora M. Vaccarino, Joseph Gleeson, Gary Mathern, Eric Courchesne, Subhojit Roy, Andrew J. Chess, Schahram Akbarian, Sara Bizzotto, Michael Coulter, Caroline Dias, Alissa D’Gama, Javier Ganz, Robert Hill, August Yue Huang, Sattar Khoshkhoo, Sonia Kim, Alice Lee, Michael Lodato, Eduardo A. Maury, Michael Miller, Rebeca Borges-Monroy, Rachel Rodin, Zinan Zhou, Craig Bohrson, Chong Chu, Isidro Cortes-Ciriano, Yanmei Dou, Alon Galor, Doga Gulhan, Minseok Kwon, Joe Luquette, Maxwell Sherman, Vinay Viswanadham, Attila Jones, Chaggai Rosenbluh, Sean Cho, Ben Langmead, Jeremy Thorpe, Jennifer Erwin, Andrew Jaffe, Michael McConnell, Rujuta Narurkar, Apua Paquola, Jooheon Shin, Richard Straub, Alexej Abyzov, Taejeong Bae, Yeongjun Jang, Yifan Wang, Cindy Molitor, Mette Peters, Sara Linker, Patrick Reed, Meiyan Wang, Alexander Urban, Bo Zhou, Xiaowei Zhu, Reenal Pattni, Aitor Serres Amero, David Juan, Irene Lobon, Tomas Marques-Bonet, Manuel Solis Moruno, Raquel Garcia Perez, Inna Povolotskaya, Eduardo Soriano, Danny Antaki, Dan Averbuj, Laurel Ball, Martin Breuss, Xiaoxu Yang, Changuk Chung, Sarah B. Emery, Diane A. Flasch, Jeffrey M. Kidd, Huira C. Kopera, Kenneth Y. Kwan, Ryan E. Mills, John B. Moldovan, Chen Sun, Xuefang Zhao, Weichen Zhou, Trenton J. Frisbie, Adriana Cherskov, Liana Fasching, Alexandre Jourdon, Sirisha Pochareddy, Soraya Scuderi
Issue&Volume: 2022-07-29
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.
DOI: abm6222
Source: https://www.science.org/doi/10.1126/science.abm6222