한빛사 논문
Taejeong Bae # 1, Liana Fasching # 2, Yifan Wang # 1, Joo Heon Shin # 3 4, Milovan Suvakov 1, Yeongjun Jang 1, Scott Norton 2, Caroline Dias 5 6, Jessica Mariani 2, Alexandre Jourdon 2, Feinan Wu 2, Arijit Panda 1, Reenal Pattni 7, Yasmine Chahine 5 6, Rebecca Yeh 5 6, Rosalinda C Roberts 8, Anita Huttner 9, Joel E Kleinman 3 10, Thomas M Hyde 3 4 10, Richard E Straub 3, Christopher A Walsh 5 6, Brain Somatic Mosaicism Network§; Alexander E Urban 7, James F Leckman 2, Daniel R Weinberger 3 4 10 11 12, Flora M Vaccarino 2 13, Alexej Abyzov 1
1Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
2Child Study Center, Yale University, New Haven, CT, USA.
3Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
4Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
5Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
6Department of Pediatrics and Department of Neurology, Harvard Medical School, Boston, MA, USA.
7Department of Psychiatry and Behavioral Sciences and Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
8Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA.
9Department of Pathology, Yale University, New Haven, CT, USA.
10Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
11Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
12Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
13Department of Neuroscience, Yale University, New Haven, CT, USA.
#Contributed equally.
Corresponding author. Email: Daniel R Weinberger, Flora M Vaccarino, Alexej Abyzov
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.
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