TY - JOUR
T1 - Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability
AU - Brain Somatic Mosaicism Network
AU - Bae, Taejeong
AU - Fasching, Liana
AU - Wang, Yifan
AU - Shin, Joo Heon
AU - Suvakov, Milovan
AU - Jang, Yeongjun
AU - Norton, Scott
AU - Dias, Caroline
AU - Mariani, Jessica
AU - Jourdon, Alexandre
AU - Wu, Feinan
AU - Panda, Arijit
AU - Pattni, Reenal
AU - Chahine, Yasmine
AU - Yeh, Rebecca
AU - Roberts, Rosalinda C.
AU - Huttner, Anita
AU - Kleinman, Joel E.
AU - Hyde, Thomas M.
AU - Straub, Richard E.
AU - Walsh, Christopher A.
AU - Weinberger, Daniel R.
AU - Urban, Alexander E.
AU - Leckman, James F.
AU - Weinberger, Daniel R.
AU - Vaccarino, Flora M.
AU - Abyzov, Alexej
N1 - Publisher Copyright:
© 2022 the authors, some rights reserved.
PY - 2022/7/9
Y1 - 2022/7/9
N2 - 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.
AB - 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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U2 - 10.1126/science.abm6222
DO - 10.1126/science.abm6222
M3 - Article
AN - SCOPUS:85135220687
SN - 0036-8075
VL - 377
SP - 511
EP - 517
JO - Science
JF - Science
IS - 6605
ER -