Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability

• DOI: 10.1126/science.abm6222
• Publication Date: 2022-07-28T18:00:23Z
• Authors: 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; ; 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-Cir...; 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
• Keywords: Aging; Enhancer Elements; General Science & Technology; Intellectual and Developmental Disabilities (IDD); Autism; 1.1 Normal biological development and functioning; Brain Somatic Mosaicism Network§; Genetic; Underpinning research; Genetics; 2.1 Biological and endogenous factors; Humans; Aetiology; Autistic Disorder; Pediatric; Whole Genome Sequencing; Human Genome; Brain; Brain Disorders; Mental Health; Enhancer Elements, Genetic; Gene Expression Regulation; Mutagenesis; Mutation; Biotechnology; Protein Binding; Transcription Factors

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 schizophrenia, and 59 autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, had 20 60 detectable single-nucleotide mutations, but ~6% harbored hundreds mutations. Hypermutability was associated age damaging in genes implicated cancers and, some brains, reflected vivo clonal expansions. Somatic duplications, likely arising during development, were found ~5% normal diseased reflecting background mutagenesis. Brains autism creating putative transcription factor binding motifs enhancer-like regions the developing brain. The top-ranked affected corresponded MEIS (myeloid ectopic viral integration site) factors, suggesting potential link between their involvement gene regulation autism.