Identification of rare de novo epigenetic variations in congenital disorders.
Identification of rare de novo epigenetic variations in congenital disorders.
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DOI：
10.1038/s41467-018-04540-x
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发表时间：
2018-05-25
影响因子：
16.6
通讯作者：
Sharp AJ
中科院分区：
文献类型：
--
作者：
Barbosa M;Joshi RS;Garg P;Martin-Trujillo A;Patel N;Jadhav B;Watson CT;Gibson W;Chetnik K;Tessereau C;Mei H;De Rubeis S;Reichert J;Lopes F;Vissers LELM;Kleefstra T;Grice DE;Edelmann L;Soares G;Maciel P;Brunner HG;Buxbaum JD;Gelb BD;Sharp AJ
某些人类特征，如神经发育障碍（ND）和先天性异常（CA），被认为主要是遗传起源。然而，即使在全基因组测序（WGS）之后，此类疾病的相当一部分仍然无法解释。我们假设某些ND-CA病例是由异常DNA甲基化导致基因组功能失调引起的。通过比较489例ND-CA患者和1534例对照者的DNA甲基化谱，我们发现表观变异在人类基因组中经常发生。从头表观变异在病例中显著富集，而RNAseq分析表明，表观变异通常对基因表达的影响与功能丧失突变相当。此外，我们检测并复制了与表观变异附近的CTCF结合位点重叠的罕见序列突变的富集，为解释非编码变异提供了依据。我们认为，外变异有助于一些不明原因的ND-CA患者的发病机制，因此可能具有诊断相关性。一部分神经发育障碍和先天性异常病例仍然没有遗传诊断。在这里，作者研究了这些病例中DNA甲基化的畸变，发现表观变异可能为一些未确诊的患者提供了解释。
Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND–CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND–CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND–CAs, and as such likely have diagnostic relevance. A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.
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影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
影响因子：
64.8
作者：
通讯作者：
--
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
影响因子：
7.7
作者：
Gutierrez-Arcelus M;Lappalainen T;Montgomery SB;Buil A;Ongen H;Yurovsky A;Bryois J;Giger T;Romano L;Planchon A;Falconnet E;Bielser D;Gagnebin M;Padioleau I;Borel C;Letourneau A;Makrythanasis P;Guipponi M;Gehrig C;Antonarakis SE;Dermitzakis ET
通讯作者：
Dermitzakis ET
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay