Department of Quantitative Health Sciences, Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Child Study Center, Yale University, New Haven, CT, USA.
Science. 2022 Jul 29;377(6605):511-517. doi: 10.1126/science.abm6222. Epub 2022 Jul 28.
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.
我们对 131 个人类大脑（44 个神经典型，19 个妥瑞氏症，9 个精神分裂症，59 个自闭症）进行了全基因组测序深度超过 200 倍的体细胞突变分析。通常，大脑中有 20 到 60 个可检测的单核苷酸突变，但大约 6%的大脑存在数百个体细胞突变。超突变性与年龄和癌症相关基因中的有害突变有关，在一些大脑中，反映了体内克隆扩展。大约 5%的正常和患病大脑中发现了体细胞重复，这可能是在发育过程中产生的，反映了背景突变。自闭症相关的大脑与在发育中的大脑中的增强子样区域中产生潜在转录因子结合基序的突变有关。排名最高的受影响基序与 MEIS（髓系异位病毒整合位点）转录因子相对应，这表明它们在基因调控中的参与与自闭症之间存在潜在联系。
