Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
Author:
Bae Taejeong1ORCID, Fasching Liana2ORCID, Wang Yifan1ORCID, Shin Joo Heon34ORCID, Suvakov Milovan1ORCID, Jang Yeongjun1ORCID, Norton Scott2ORCID, Dias Caroline56, Mariani Jessica2, Jourdon Alexandre2ORCID, Wu Feinan2ORCID, Panda Arijit1ORCID, Pattni Reenal7ORCID, Chahine Yasmine56, Yeh Rebecca56, Roberts Rosalinda C.8, Huttner Anita9, Kleinman Joel E.310ORCID, Hyde Thomas M.3410ORCID, Straub Richard E.3ORCID, Walsh Christopher A.56ORCID, Urban Alexander E.7ORCID, Leckman James F.2ORCID, Weinberger Daniel R.34101112ORCID, Vaccarino Flora M.213ORCID, Abyzov Alexej1ORCID, Walsh Christopher A., Park Peter J., Sestan Nenad, Weinberger Daniel, Moran John V., Gage Fred H., Vaccarino Flora M., Gleeson Joseph, Mathern Gary, Courchesne Eric, Roy Subhojit, Chess Andrew J., Akbarian Schahram, Bizzotto Sara, Coulter Michael, Dias Caroline, D’Gama Alissa, Ganz Javier, Hill Robert, Huang August Yue, Khoshkhoo Sattar, Kim Sonia, Lee Alice, Lodato Michael, Maury Eduardo A., Miller Michael, Borges-Monroy Rebeca, Rodin Rachel, Zhou Zinan, Bohrson Craig, Chu Chong, Cortes-Ciriano Isidro, Dou Yanmei, Galor Alon, Gulhan Doga, Kwon Minseok, Luquette Joe, Sherman Maxwell, Viswanadham Vinay, Jones Attila, Rosenbluh Chaggai, Cho Sean, Langmead Ben, Thorpe Jeremy, Erwin Jennifer, Jaffe Andrew, McConnell Michael, Narurkar Rujuta, Paquola Apua, Shin Jooheon, Straub Richard, Abyzov Alexej, Bae Taejeong, Jang Yeongjun, Wang Yifan, Molitor Cindy, Peters Mette, Linker Sara, Reed Patrick, Wang Meiyan, Urban Alexander, Zhou Bo, Zhu Xiaowei, Pattni Reenal, Serres Amero Aitor, Juan David, Lobon Irene, Marques-Bonet Tomas, Solis Moruno Manuel, Garcia Perez Raquel, Povolotskaya Inna, Soriano Eduardo, Antaki Danny, Averbuj Dan, Ball Laurel, Breuss Martin, Yang Xiaoxu, Chung Changuk, Emery Sarah B., Flasch Diane A., Kidd Jeffrey M., Kopera Huira C., Kwan Kenneth Y., Mills Ryan E., Moldovan John B., Sun Chen, Zhao Xuefang, Zhou Weichen, Frisbie Trenton J., Cherskov Adriana, Fasching Liana, Jourdon Alexandre, Pochareddy Sirisha, Scuderi Soraya,
Affiliation:
1. Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. 2. Child Study Center, Yale University, New Haven, CT, USA. 3. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA. 4. Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. 5. Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, USA. 6. Department of Pediatrics and Department of Neurology, Harvard Medical School, Boston, MA, USA. 7. Department of Psychiatry and Behavioral Sciences and Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. 8. Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. 9. Department of Pathology, Yale University, New Haven, CT, USA. 10. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA. 11. Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA. 12. Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA. 13. Department of Neuroscience, Yale University, New Haven, CT, USA.
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.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Multidisciplinary
Cited by
33 articles.
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