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Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability.
Science ( IF 56.9 ) Pub Date : 2022-07-28 , DOI: 10.1126/science.abm6222
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 , , Alexander E Urban 7 , James F Leckman 2 , Daniel R Weinberger 3, 4, 10, 11, 12 , Flora M Vaccarino 2, 13 , Alexej Abyzov 1
Affiliation  

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.

中文翻译:

对 131 个人类大脑体细胞突变的分析揭示了与衰老相关的超突变性。

我们在全基因组测序深度超过 200 倍后,分析了 131 个人类大脑(44 个神经正常大脑、19 个抽动秽语综合征患者、9 个精神分裂症患者和 59 个自闭症患者)的体细胞突变。通常,大脑有 20 到 60 个可检测的单核苷酸突变,但约 6% 的大脑含有数百个体细胞突变。超可变性与年龄和与癌症有关的基因的破坏性突变有关,并且在某些大脑中反映了体内克隆扩张。在约 5% 的正常和患病大脑中发现了可能在发育过程中出现的体细胞重复,这反映了背景突变。患有自闭症的大脑与在发育中的大脑的增强子样区域中产生假定的转录因子结合基序的突变有关。排名靠前的受影响基序对应于 MEIS(髓样异位病毒整合位点)转录因子,表明它们参与基因调控与自闭症之间存在潜在联系。
更新日期:2022-07-28
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