An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.
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DOI：
10.1038/s41588-018-0130-z
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发表时间：
2018-07
期刊：
影响因子：
30.8
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Chen S;Fragoza R;Klei L;Liu Y;Wang J;Roeder K;Devlin B;Yu H
识别与疾病相关的错义突变仍然是一个挑战，特别是在大规模测序研究中。在这里，我们建立了一种实验和计算集成的方法来研究错义突变在人类相互作用组网络背景下的功能影响，并通过分析在自闭症受试者及其未受影响的兄弟姐妹中发现的约 2,000 个从头错义 (dnMis) 突变来测试我们的方法。干扰相互作用的 dnMis 突变在自闭症先证者中更为常见，这些突变主要影响中枢蛋白，并且与未受影响的兄弟姐妹相比，它们破坏的中枢相互作用比例明显更高。此外，它们往往会破坏先前与自闭症有关的基因的相互作用，提供补充证据，加强先前确定的关联并促进新关联的发现。重要的是，通过分析六种疾病的 dnMis 数据，我们证明我们的相互作用组扰动方法提供了一个通用框架，用于识别和优先考虑导致人类疾病风险的错义突变。
Identifying disease-associated missense mutations remains a challenge, especially in large-scale sequencing studies. Here we establish an experimentally and computationally integrated approach to investigate the functional impact of missense mutations in the context of the human interactome network and test our approach by analyzing ~2,000 de novo missense (dnMis) mutations found in autism subjects and their unaffected siblings. Interaction-disrupting dnMis mutations are more common in autism probands, these mutations principally affect hub proteins, and they disrupt a significantly higher fraction of hub interactions than in unaffected siblings. Additionally, they tend to disrupt interactions involving genes previously implicated in autism, providing complementary evidence that strengthens previously identified associations and enhances discovery of new ones. Importantly, by analyzing dnMis data from six disorders, we demonstrate that our interactome perturbation approach offers a generalizable framework for identifying and prioritizing missense mutations that contribute risk to human disease.
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影响因子：
--
作者：
Das J;Yu H
通讯作者：
Yu H
影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
错义突变热点识别神经发育障碍基因和功能域
影响因子：
25
作者：
Geisheker MR;Heymann G;Wang T;Coe BP;Turner TN;Stessman HAF;Hoekzema K;Kvarnung M;Shaw M;Friend K;Liebelt J;Barnett C;Thompson EM;Haan E;Guo H;Anderlid BM;Nordgren A;Lindstrand A;Vandeweyer G;Alberti A;Avola E;Vinci M;Giusto S;Pramparo T;Pierce K;Nalabolu S;Michaelson JJ;Sedlacek Z;Santen GWE;Peeters H;Hakonarson H;Courchesne E;Romano C;Kooy RF;Bernier RA;Nordenskjöld M;Gecz J;Xia K;Zweifel LS;Eichler EE
通讯作者：
Eichler EE
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
14.9
作者：
Basu SN;Kollu R;Banerjee-Basu S
通讯作者：
Banerjee-Basu S