High prevalence of focal and multi-focal somatic genetic variants in the human brain.
High prevalence of focal and multi-focal somatic genetic variants in the human brain.
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DOI：
10.1038/s41467-018-06331-w
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发表时间：
2018-10-15
影响因子：
16.6
通讯作者：
Chinnery PF
中科院分区：
文献类型：
--
作者：
Keogh MJ;Wei W;Aryaman J;Walker L;van den Ameele J;Coxhead J;Wilson I;Bashton M;Beck J;West J;Chen R;Haudenschild C;Bartha G;Luo S;Morris CM;Jones NS;Attems J;Chinnery PF
干细胞分裂过程中的体细胞突变是几种癌症的原因。原则上，在伴随人类大脑发育的强烈细胞增殖过程中可能发生类似的过程，导致区域分布的突变灶的积累。使用双平台>5000倍深度测序173个成人大脑样本中的102个基因，我们检测并验证了54个大脑中27个的体细胞突变。使用神经发育的数学模型和近似贝叶斯推理，我们预测病理突变神经元的宏观岛屿在一般人群中可能很常见。检测到的突变谱还包括DNMT3A和TET2，它们可能起源于血细胞谱系。总之，这些研究结果建立了发育诱变作为神经退行性疾病的潜在机制，并提供了一种新的机制，在散发病例的区域发病和局灶性病理。与癌症类似，体细胞突变可能导致神经退行性疾病。在这里，作者对173个成人大脑中的102个基因进行了超深度测序，检测了54个大脑中的体细胞突变，并开发了一个数学模型来估计人脑中突变灶的频率。
Somatic mutations during stem cell division are responsible for several cancers. In principle, a similar process could occur during the intense cell proliferation accompanying human brain development, leading to the accumulation of regionally distributed foci of mutations. Using dual platform >5000-fold depth sequencing of 102 genes in 173 adult human brain samples, we detect and validate somatic mutations in 27 of 54 brains. Using a mathematical model of neurodevelopment and approximate Bayesian inference, we predict that macroscopic islands of pathologically mutated neurons are likely to be common in the general population. The detected mutation spectrum also includes DNMT3A and TET2 which are likely to have originated from blood cell lineages. Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders, and provide a novel mechanism for the regional onset and focal pathology in sporadic cases. Similar to cancers, somatic mutations might lead to neurodegenerative diseases. Here, the authors perform ultra-deep sequencing of 102 genes in 173 adult human brains, detect somatic mutations in 54 brains, and develop a mathematical model to estimate the frequency of mutated foci in human brains.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
影响因子：
7
作者：
Keogh MJ;Wei W;Wilson I;Coxhead J;Ryan S;Rollinson S;Griffin H;Kurzawa-Akanbi M;Santibanez-Koref M;Talbot K;Turner MR;McKenzie CA;Troakes C;Attems J;Smith C;Al Sarraj S;Morris CM;Ansorge O;Pickering-Brown S;Ironside JW;Chinnery PF
通讯作者：
Chinnery PF
来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.